What does transplant rejection mean?
Transplant rejection
Bone marrow transplant can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's hematopoietic stem cells—the reservoir of stem cells replenishing exhausted blood cells including white blood cells forming the immune system—must be of the individual who donated the organ or of an identical twin or a clone. There is a risk of graft-versus-host disease (GVHD), however, whereby mature lymphocytes entering with marrow recognize the new host tissues as foreign and destroy them.
Organ transplantation in Israel
Organ transplantation in Israel has historically been low compared to other Western countries due to a common belief that organ donation is prohibited under Jewish law. This changed with the passage of new organ donation laws in 2008. If two patients have the same medical need, priority will now go to the patient who has signed an organ donor card, or whose family members have donated an organ (though medical necessity still takes precedence). This policy was nicknamed don't give, don't get. The law also defines "brain death" as an indication of death for all legal purposes, including organ donation. Additionally the law provides financial reimbursement to living donors for medical expenses due to donation and lost time at work. Organ trafficking is explicitly banned. Health insurance plans can no longer reimburse patients who go abroad to receive transplants.
Hybrid resistance
In a case of BM transplantation, where the F1 generation arise from two individuals with H2 and H2 MHC I phenotype. The F1 generation will be H2. It means that there are NK cells in F1 generation, that recognize H2 aleles as a self MHC I and there has to be signaling through both of them to inhibition of NKs. But from the P can be only H2 or H2 transplanted, so the NKs won´t be inhibited enough, because they need signals from both MHC I aleles. This event leads to parental graft rejection.
Transplant rejection
As a cell is indicated by the prefix "cyto", a cytotoxic influence destroys the cell. Alloreactive killer T cells, also called cytotoxic T lymphocytes (CTLs), have CD8 receptors that dock to the transplanted tissue's MHC class I molecules, which display the donor's self peptides. (In the living donor, such presentation of "self" antigens helped maintain "self" tolerance.) Thereupon, the T cell receptors (TCRs) of the killer T cells recognize their matching epitope, and trigger the target cell's programmed cell death by apoptosis.
Uterus transplantation
The transplant is intended to be temporary – the recipient will undergo a hysterectomy after one or two successful pregnancies. This is to avoid the need for her to take immunosuppressive drugs for life with a consequent increased risk of infection.
Intestine transplantation
There are four Medicare and Medicaid-approved indications for intestine transplantation: a loss of two of the six major routes of venous access, multiple episodes of catheter-associated life-threatening sepsis, fluid and electrolyte abnormalities in the face of maximal medical therapy, and PN-associated liver disease. Transplants may also be performed if the growth and development of a pediatric patient fails to ensue, or in extreme circumstances for patients with an exceptionally low quality of life on PN. A multidisciplinary team consisting of transplant surgeons, gastroenterologists, dieticians, anesthesiologists, psychiatrists, financial representatives, and other specialists should be consulted to evaluate the treatment plan and ensure transplantation is the patient's best option. Psychological preparations should be made for the transplant team and patient as well. Early referral requires trust between all parties involved in the operation to ensure that a rush to judgment does not lead to a premature transplant.
Hand transplantation
A hand transplant was performed in Ecuador in 1964, but the patient suffered from transplant rejection after only two weeks due to the primitive nature of the immune-suppressing medications at that time.
Organ transplantation
The existence and distribution of organ transplantation procedures in developing countries, while almost always beneficial to those receiving them, raise many ethical concerns. Both the source and method of obtaining the organ to transplant are major ethical issues to consider, as well as the notion of distributive justice. The World Health Organization argues that transplantations promote health, but the notion of "transplantation tourism" has the potential to violate human rights or exploit the poor, to have unintended health consequences, and to provide unequal access to services, all of which ultimately may cause harm. Regardless of the "gift of life", in the context of developing countries, this might be coercive. The practice of coercion could be considered exploitative of the poor population, violating basic human rights according to Articles 3 and 4 of the Universal Declaration of Human Rights. There is also a powerful opposing view, that trade in organs, if properly and effectively regulated to ensure that the seller is fully informed of all the consequences of donation, is a mutually beneficial transaction between two consenting adults, and that prohibiting it would itself be a violation of Articles 3 and 29 of the Universal Declaration of Human Rights.
Brain transplant
A brain transplant or whole-body transplant is a procedure in which the brain of one organism is transplanted into the body of another organism. It is a procedure distinct from head transplantation, which involves transferring the entire head to a new body, as opposed to the brain only. Theoretically, a person with advanced organ failure could be given a new and functional body while keeping their own personality, memories, and consciousness through such a procedure.
Alloimmunity
Hyperacute and accelerated rejection is antibody-mediated immune response to the allograft. Recipient’s blood already contains circulating antibodies before the transplantation – either IgM or antibodies incurred by previous immunization (e.g. by repeated blood transfusion). In case of hyperacute rejection, antibodies activate complement; moreover, the reaction can be enhanced by neutrophils. This type of rejection is very fast, the graft is rejected in a few minutes or hours after the transplantation. Accelerated rejection leads to phagocyte and NK cell activation (not of the complement) through their Fc receptors that bind Fc parts of antibodies. Graft rejection occurs within 3 to 5 days. This type of rejection is a typical response to xenotransplants.
Transplant rejection
While kidneys can routinely be obtained from human donors, most organs are in short supply leading to consideration of xenotransplants from other species. Pigs are especially likely sources for xenotransplants, chosen for the anatomical and physiological characteristics they share with humans. However, the sugar galactose-alpha-1,3-galactose (αGal) has been implicated as a major factor in hyperacute rejection in xenotransplantation. Unlike virtually all other mammals, humans and other primates do not make αGal, and in fact recognize it as an antigen. During transplantation, xenoreactive natural antibodies recognize αGal on the graft endothelium as an antigen, and the resulting complement-mediated immune response leads to a rejection of the transplant.
Transplant rejection
The most important factors are that the recipient not have produced isohemagglutinins, and that they have low levels of T cell-independent antigens. UNOS regulations allow for ABOi transplantation in children under two years of age if isohemagglutinin titers are 1:4 or below, and if there is no matching ABOc recipient. Studies have shown that the period under which a recipient may undergo ABOi transplantation may be prolonged by exposure to nonself A and B antigens. Furthermore, should the recipient (for example, type B-positive with a type AB-positive graft) require eventual retransplantation, the recipient may receive a new organ of either blood type.
Organ gifting
Reciprocity tends to be discouraged in contemporary organ gifting, thus creating an irresoluble sense of debt in the receiver. This separation of the donor from the object being given was not always implemented, and in earlier cases of organ transplantation the receiver could obtain information from the donor and even meet. As Holtkamp (2002) has argued, this arrangement created a feeling of debt in the receiver (and close kin) and led to the creation of obligations. The discouragement of reciprocal relationships between giver and receiver is produced through what Sharp (2001) has labeled etiquettes of dehumanization where the identities of the donors are removed from the organs.
Piercing migration
Rejection rate is a term used by the piercing industry. It applies to the chance of a piercing being forced out by the body. This is a body's natural reaction to a foreign object being inserted into the skin. This behavior can be witnessed with other objects such as splinters, road rash, or infections. With surface piercings being closer to the surface of the skin, the tendency to reject is higher, as it is easier for the body to force the jewelry out.
Transplant rejection
Rejection is an adaptive immune response via cellular immunity (mediated by killer T cells inducing apoptosis of target cells) as well as humoral immunity (mediated by activated B cells secreting antibody molecules), though the action is joined by components of innate immune response (phagocytes and soluble immune proteins). Different types of transplanted tissues tend to favor different balances of rejection mechanisms.
Organ transplantation
The more likely accounts of early transplants deal with skin transplantation. The first reasonable account is of the Indian surgeon Sushruta in the 2nd century BC, who used autografted skin transplantation in nose reconstruction, a rhinoplasty. Success or failure of these procedures is not well documented. Centuries later, the Italian surgeon Gasparo Tagliacozzi performed successful skin autografts; he also failed consistently with allografts, offering the first suggestion of rejection centuries before that mechanism could possibly be understood. He attributed it to the "force and power of individuality" in his 1596 work "De Curtorum Chirurgia per Insitionem".
Intestine transplantation
Donated intestines, like all organs, should be matched to a recipient prior to recovery, as to prepare him or her and minimize the time the organ spends outside the body. Potential recipients are placed on the International Intestinal Transplant Registry (ITR), where they contribute to the world's growing understanding of intestine transplantation. Before a transplant may be performed, an organ must first be located. In the United States, the matching of all organs is coordinated by the United Network for Organ Sharing (UNOS). The standard intestinal donor is deceased with a diagnosis of brain death. In terms of transplant outcomes, brain-dead donors are highly preferable to donors who have suffered cardiopulmonary death. If respiration can be assisted by a ventilator, brain-dead donors may exhibit maintainable cardiac, endocrine, and excretory function. If appropriately managed, the continuation of blood flow and bodily metabolism allows for healthier organs for procurement and additional time to prepare recipients for transplant. Furthermore, terminal ileum recovery from living donors is possible., and a laparoscopic technique is being developed to harvest limited sections of small bowel from living donors. When determining potential donor-recipient matches, important characteristics include donor size, age, tissue quality, and ABO and histo-compatibility. If the intestine is too large, it may be not transplantable into young or small patients. Ideally, intestines should be selected from donors of lighter weight than the proposed recipients to ensure simple closure of the abdominal wound. If a patient is too young or too old, they may not be hardy enough to survive the operation and recovery period. If the donor and recipient organs do not meet compatibility requirements, the threat of organ rejection by the body is all but certain.
Head transplant
Of these challenges, dealing with blood supply and transplant rejection have been addressed in the field of transplant medicine generally, making transplantation of several types of organs fairly routine; however in a field as common as liver transplantation around a quarter of organs are rejected within the first year and overall mortality is still much higher than the general population. The challenge of grafting the nervous system remained in early stages of research .
Transplanting
Different species and varieties react differently to transplanting; for some, it is not recommended. In all cases, avoiding "transplant shock"—the stress or damage received in the process—is the principal concern. Plants raised in protected conditions usually need a period of acclimatization, known as hardening off (see also frost hardiness). Also, root disturbance should be minimized. The stage of growth at which transplanting takes place, the weather conditions during transplanting, and treatment immediately after transplanting are other important factors.
Xenotransplantation
To date no xenotransplantation trials have been entirely successful due to the many obstacles arising from the response of the recipient’s immune system. "Xenozoonoses" are one of the biggest threats to rejections, as they are xenogenetic infections. The introduction of these microorganisms are a big issue that lead to the fatal infections and then rejection of the organs. This response, which is generally more extreme than in allotransplantations, ultimately results in rejection of the xenograft, and can in some cases result in the immediate death of the recipient. There are several types of rejection organ xenografts are faced with, these include hyperacute rejection, acute vascular rejection, cellular rejection, and chronic rejection.
Transplant surgeon
There are distinct parameters for who is eligible for transplantation of the different organs. Broadly speaking (this is not meant to be exhaustive), these include: age, how long they have been on the waiting list, how urgently they need the organ (which is often related to how long they've been on the list, and whether they are actually in end-stage disease, which has its own laboratory and functional criteria per organ); their prognosis (how stable they are now- whether they can survive major invasive surgery and the anesthesia and post-op period, and how they have been, and how they likely will fare with and/or without the organ, versus with other therapies that are not transplantation- such as continued dialysis or getting an artificial heart or left ventricular assist device).
Organ donation
A relatively new field of transplantation has reinvigorated the debate. Xenotransplantation, or the transfer of animal (usually pig) organs into human bodies, promises to eliminate many of the ethical issues, while creating many of its own. While xenotransplantation promises to increase the supply of organs considerably, the threat of organ transplant rejection and the risk of xenozoonosis, coupled with general anathema to the idea, decreases the functionality of the technique. Some animal rights groups oppose the sacrifice of an animal for organ donation and have launched campaigns to ban them.
Known Space
On Earth in the mid-21st century, it became possible to transplant any organ from any person to another, with the exception of brain and central nervous system tissue. Individuals were categorized according to their so-called "rejection spectrum" which allowed doctors to counter any immune system responses to the new organs, allowing transplants to "take" for life. It also enabled the crime of "organlegging" which lasted well into the 24th century.
Non-heart-beating donation
The main obstacle to accepting the proposal is securing the acceptance of the public to allow physicians to cause the death of (which is to say kill) patients to obtain transplantable organs. Proponents of the proposal contend that robust consent requirements can provide the public with the assurance against exploitation that the dead donor rule and the prohibition on killing are designed to provide. Others deny this. Thus the question can be posed: "Given the difficulties our society is likely to experience in trying to openly adjudicate these disparate views [of accepting or rejecting the prohibition on physicians killing for transplantation], why not simply go along with the quieter strategy of policy creep? It seems to be getting us where we want to go, albeit slowly. Besides, total candor is not always compatible with public policy (Calabresi G and Bobbitt P. "Tragic Choices". New York: Norton,1978)." The debate continues unresolved.
History and naming of human leukocyte antigens
In the accompanying figure, two similar haplotypes (unknown to early clinicians) are identical, except for the one "antigen" in the top haplotype. The transplant may not be rejected, but if rejection does occur that allotypic protein, the allo"antigen", in the donor tissue may have induced the dominant allo-reactive antibody in the recipient.
Hand transplantation
Hand transplantation is a surgical procedure to transplant a hand from one human to another. The "donor" hand usually comes from a brain-dead donor and is transplanted to a recipient who has lost one or both hands/arms. Most hand transplants to date have been performed on below elbow amputees, although above elbow transplants are gaining popularity. Hand transplants were the first of a new category of transplants where multiple organs are transplanted as a single functional unit, now termed "Vascularized Composite Allotransplantation" or VCA.
Organ transplantation
In an April 2008 article in "The Guardian", Steven Tsui, the head of the transplant team at Papworth Hospital in the UK, is quoted in raising the ethical issue of not holding out false hope. He stated, "Conventionally we would say if people's life expectancy was a year or less we would consider them a candidate for a heart transplant. But we also have to manage expectations. If we know that in an average year we will do 30 heart transplants, there is no point putting 60 people on our waiting list, because we know half of them will die and it's not right to give them false hope."
Liver transplantation
Three types of graft rejection may occur: hyperacute rejection, acute rejection, and chronic rejection.Before transplantation, liver-support therapy might be indicated (bridging-to-transplantation). Artificial liver support like liver dialysis or bioartificial liver support concepts are currently under preclinical and clinical evaluation. Virtually all liver transplants are done in an orthotopic fashion; that is, the native liver is removed and the new liver is placed in the same anatomic location. The transplant operation can be conceptualized as consisting of the hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the postimplantation phase. The operation is done through a large incision in the upper abdomen. The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, hepatic vein and portal vein. Usually, the retrohepatic portion of the inferior vena cava is removed along with the liver, although an alternative technique preserves the recipient's vena cava ("piggyback" technique).
Brain transplant
The brain was thought to be an immunologically privileged organ, so rejection would not be a problem. (When other organs are transplanted, aggressive rejection can occur; this is a major difficulty with kidney and liver transplants. Immune cells of the CNS contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood, so the transplanted brain would not be unhindered from the transplant.)
Transplant rejection
The first successful organ transplant, performed in 1954 by Joseph Murray, involved identical twins, and so no rejection was observed. Otherwise, the number of mismatched gene variants, namely alleles, encoding cell surface molecules called major histocompatibility complex (MHC), classes I and II, correlate with the rapidity and severity of transplant rejection. In humans MHC is also called human leukocyte antigen (HLA).
Transplant rejection
Dendritic cells (DCs), which are the primary antigen-presenting cells (APCs), of the donor tissue migrate to the recipient's peripheral lymphoid tissue (lymphoid follicles and lymph nodes), and present the donor's "self" peptides to the recipient's lymphocytes (immune cells residing in lymphoid tissues). Lymphocytes include two classes that enact adaptive immunity, also called specific immunity. Lymphocytes of specific immunity T cells—including the subclasses helper T cells and killer T cells—and B cells.
Thalachallour Mohanakumar
During his time at Washington University, Mahonakumar has made numerous contributions in his success of clinical and research programs, including the immunological mechanisms underlying transplant rejection. Along with heading transplant programs, he also supervises islet location and is the Director of Histocompatibility, an important component of bone marrow and organ transplantation. He has received accomplishments, awards, and citations from the American Society of Histocompatibility and Immunogenetics, American Society of Transplantation, and the Juvenile Diabetes Research Foundation. In his research, he has published more than 350 manuscripts and has served on many National Institutes of Health (NIH) study sections. Mahonakumar and his research group have been studying the processes of lung transplant rejection for more than 20 years. Recently, they found a possible diagnosis for chronic lung allograft dysfunction (CLAD) by monitoring proteins, such as Zinc finger and BYB domain-containing protein 7A (ZBTB7A).
Organ transplantation
Transplantation medicine is one of the most challenging and complex areas of modern medicine. Some of the key areas for medical management are the problems of transplant rejection, during which the body has an immune response to the transplanted organ, possibly leading to transplant failure and the need to immediately remove the organ from the recipient. When possible, transplant rejection can be reduced through serotyping to determine the most appropriate donor-recipient match and through the use of immunosuppressant drugs.
Uterus transplantation
The uterine transplant is the surgical procedure whereby a healthy uterus is transplanted into an organism of which the uterus is absent or diseased. As part of normal mammalian sexual reproduction, a diseased or absent uterus does not allow normal embryonic implantation, effectively rendering the female infertile. This phenomenon is known as absolute uterine factor infertility (AUFI). Uterine transplant is a potential treatment for this form of infertility.
Intestine transplantation
Failure of the small intestine would be life-threatening due to the inability to absorb nutrients, fluids, and electrolytes from food. Without these essential substances and the ability to maintain energy balances, homeostasis cannot be maintained and one's prognosis will be dismal. Causes of intestinal failure may be clinically complex, and may result from a combination of nutritional, infectious, traumatic, and metabolic complications that affect ordinary anatomy and physiology. Many underlying conditions that serve as precursors to failure are genetic or congenital in nature. For example, severe inflammation, ulceration, bowel obstruction, fistulation, perforation, or other pathologies of Crohn's disease may severely compromise intestinal function. Despite the danger these conditions may pose in themselves, they may lead to even further, more serious complications that necessitate replacement of the diseased intestine. The single leading cause for an intestinal transplant is affliction with short bowel syndrome, oftentimes a secondary condition of some other form of intestinal disease. Short-bowel syndrome was the cause for 73% of American intestinal transplantations in 2008, followed by functional bowel problems for 15% and other causes representing 12% of cases. Natural SBS is mercifully rare, estimated to be 3 per 100,000 births. Surgical removal is the most common cause, performed as a treatment for various gastroenterological and congenital conditions such as Crohn's disease, necrotizing enterocolitis, mesenteric ischemia, motility disorder, omphalocele/gastroschisis, tumors, and volvulus.
Transplant rejection
Gene therapy is another method that can be used. In this method, the genes that cause the body to reject transplants would be deactivated. Research is still being conducted, and no gene therapies are being used to date to treat patients. Current research tends to focus on Th1 and Th17 which mediate allograft rejection via the CD4 and CD8 T cells
Heart transplantation
Norman Shumway performed the first adult heart transplant in the United States on January 6, 1968, at the Stanford University Hospital. A team led by Donald Ross performed the first heart transplant in the United Kingdom on May 3, 1968. An allotransplantation is the technical term for a transplant from a non-genetically identical individual of the same species. Brain death is the current ethical standard for when a heart donation can be allowed.
Allotransplantation
An immune response against an allograft or xenograft is termed rejection. An allogenic bone marrow transplant can result in an immune attack, called graft-versus-host disease.
Syngenic
A tumor isolated from an organism and transplanted in its syngeneic organism elicits an immune reaction leading to rejection, whereas a normal transplanted tissue won't. This signifies that tumor cells show antigens which are completely new or modified. This forms the basis of Tumor Specific Transplantation Antigens(TSTA) or Tumor Associated Transplant Antigens(TATA).
Kidney transplantation
The major barrier to organ transplantation between genetically non-identical patients lay in the recipient's immune system, which would treat a transplanted kidney as a "non-self" and immediately or chronically reject it. Thus, having medications to suppress the immune system was essential. However, suppressing an individual's immune system places that individual at greater risk of infection and cancer (particularly skin cancer and lymphoma), in addition to the side effects of the medications.
Corneal transplantation
There is a risk of cornea rejection, which occurs in about 20% of cases. Graft failure can occur at any time after the cornea has been transplanted, even years or decades later. The causes can vary, though it is usually due to new injury or illness. Treatment can be either medical or surgical, depending on the individual case. An early, technical cause of failure may be an excessively tight stitch cheesewiring through the sclera.
ABO-incompatible transplantation
Limited success has been achieved in ABOi heart transplantation in adults, though this requires that the adult recipients have low levels of anti-A or anti-B antibodies. Some organs are more conducive to adult ABOi transplant than others, such as liver and kidney. Adults are significantly likely to suffer from hyperacute rejection, thrombosis, or death, but could be considered to be an acceptable risk if the alternative is otherwise death. In the case of ABOi renal transplantation, aggressive antibody removal is required, along with supplemental medication, with the resulting condition being termed "accommodation." While such recipients are more likely to require re-transplantation early on, long-term graft survival is similar to recipients who receive ABOc kidneys.
Intestine transplantation
Intestinal transplants are highly susceptible to infection even more so than the standard immunocompromised recipient of other organs due to the great composition and variety of the gut flora. A complex assortment of microorganisms inhabits the human digestive tract, with concentrations of up to 10–10 CFU/mL in the jejunoileum and 10–10 CFU/mL in the colon. While suppression of the immune system may prevent immune attack on the new allograft, it may also prevent the immune system's ability to keep certain gut microbial populations in line. Despite pre and post-decontamination of the transplant, recipients are at risk of local and systemic infection by both natural and external flora. The common symptom of graft dysfunction, whether due to infection, rejection, or some other condition, is diarrhea.
Organ transplantation
A "paired-exchange" is a technique of matching willing living donors to compatible recipients using serotyping. For example, a spouse may be willing to donate a kidney to their partner but cannot since there is not a biological match. The willing spouse's kidney is donated to a matching recipient who also has an incompatible but willing spouse. The second donor must match the first recipient to complete the pair exchange. Typically the surgeries are scheduled simultaneously in case one of the donors decides to back out and the couples are kept anonymous from each other until after the transplant.
Kidney transplantation
Some studies seem to suggest that the longer a patient is on dialysis before the transplant, the less time the kidney will last. It is not clear why this occurs, but it underscores the need for rapid referral to a transplant program. Ideally, a kidney transplant should be pre-emptive, i.e., take place before the patient begins dialysis. The reason why kidneys fail over time after transplantation has been elucidated in recent years. Apart from recurrence of the original kidney disease, also rejection (mainly antibody-mediated rejection) and progressive scarring (multifactorial) play a decisive role. Avoiding rejection by strict medication adherence is of utmost importance to avoid failure of the kidney transplant.
Xenotransplantation
Scientific interest in xenotransplantation declined when the immunological basis of the organ rejection process was described. The next waves of studies on the topic came with the discovery of immunosuppressive drugs. Even more studies followed Dr. Joseph Murray's first successful renal transplantation in 1954 and scientists, facing the ethical questions of organ donation for the first time, accelerated their effort in looking for alternatives to human organs.
Hand transplantation
The recipient of a hand transplant needs to take immunosuppressive drugs similar to other transplants such as kidneys or livers, as the body's natural immune system will try to reject, or destroy, the hand. These drugs cause the recipient to have a weaker immune system which may lead to an increased risk of infections and some cancers. There have been many advances in solid organ transplantation over the years that have made these medications quite tolerable.
Liver transplantation
Importantly, many contraindications to liver transplantation are considered reversible; a person initially deemed "transplant-ineligible" may later become a favorable candidate if their situation changes. Some examples include:
Heart transplantation
People who have had heart transplants are monitored in various ways to test for the development of rejection.
Transplantable organs and tissues
"Kidney transplantation" is the organ transplant of a kidney in a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantation depending on the source of the recipient organ. Living-donor renal transplants are further characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on whether a biological relationship exists between the donor and recipient.
Edward Stinson (surgeon)
The research provided the basis of knowledge for the world's first heart transplant by Christiaan Barnard and the later Stanford transplant programmes over the following decades when such programmes were shut down elsewhere. The importance of understanding the physiology of the cardiac homograft and the process of rejection was accepted as fundamental to understanding the best way to detect and treat rejection. The issue of accurately detecting early rejection, of which Stinson was also involved, came later.
Lung transplantation
Chronic rejection, meaning repeated bouts of rejection symptoms beyond the first year after the transplant surgery, occurs in approximately 50% of patients. Such chronic rejection presents itself as bronchiolitis obliterans, or less frequently, atherosclerosis.
These statistics are based on data from 2008. The source data made no distinction between living and deceased donor organs, nor was any distinction made between lobar, single, and double lung transplants.
Ascites
Ascites that is refractory to medical therapy is considered an indication for liver transplantation. In the United States, the MELD score (online calculator) is used to prioritize people for transplantation.
Transplant rejection
When the paratope of Ig class "gamma" (IgG) binds its matching epitope, IgG's Fc region conformationally shifts and can host a complement protein, initiating the complement cascade that terminates by punching a hole in a cell membrane. With many holes so punched, fluid rushes into the cell and ruptures it.
Kidney transplantation
It was not until June 17, 1950, when a successful transplant could be performed on Ruth Tucker, a 44-year-old woman with polycystic kidney disease, by Dr. Richard Lawler at Little Company of Mary Hospital in Evergreen Park, Illinois. Although the donated kidney was rejected ten months later because no immunosuppressive therapy was available at the time—the development of effective antirejection drugs was years away—the intervening time gave Tucker's remaining kidney time to recover and she lived another five years.
Ethics of organ transplantation
Regardless of the “gift of life”, in the context of developing countries, this might be coercive. The practice of coercion could be considered exploitative of the poor population, violating basic human rights according to Articles 3 and 4 of the Universal Declaration of Human Rights. For example, in the history of major transplant countries, organs from executed prisoners are used to develop their techniques. This practice was condemned by bioethicists and was gradually abandoned and replaced by donation systems
Alloimmunity
Acute rejection is caused by antigen-specific Th1 and cytotoxic T-lymphocytes. They recognize transplanted tissue because of expression of alloantigens. A transplant is rejected during first several days or weeks after transplantation.
Organ transplantation
The most important factors are that the recipient not have produced isohemagglutinins, and that they have low levels of T cell-independent antigens. United Network for Organ Sharing (UNOS) regulations allow for ABOi transplantation in children under two years of age if isohemagglutinin titers are 1:4 or below, and if there is no matching ABOc recipient. Studies have shown that the period under which a recipient may undergo ABOi transplantation may be prolonged by exposure to nonself A and B antigens. Furthermore, should the recipient (for example, type B-positive with a type AB-positive graft) require eventual retransplantation, the recipient may receive a new organ of either blood type.
Kidney transplantation
In an effort to reduce the risk of rejection during incompatible transplantation, ABO-incompatible and densensitization protocols utilizing intravenous immunoglobulin (IVIG) have been developed, with the aim to reduce ABO and HLA antibodies that the recipient may have to the donor.
Organ transplantation
An allograft is a transplant of an organ or tissue between two genetically non-identical members of the same species. Most human tissue and organ transplants are allografts. Due to the genetic difference between the organ and the recipient, the recipient's immune system will identify the organ as foreign and attempt to destroy it, causing transplant rejection. The risk of transplant rejection can be estimated by measuring the Panel reactive antibody level.
Major histocompatibility complex
In a transplant procedure, as of an organ or stem cells, MHC molecules act themselves as antigens and can provoke immune response in the recipient, thus causing transplant rejection. MHC molecules were identified and named after their role in transplant rejection between mice of different strains, though it took over 20 years to clarify MHC's role in presenting peptide antigens to cytotoxic T lymphocytes (CTLs).
Organ transplantation
Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transported from a donor site to another location. Organs and/or tissues that are transplanted within the same person's body are called autografts. Transplants that are recently performed between two subjects of the same species are called allografts. Allografts can either be from a living or cadaveric source.
Hematopoietic stem cell transplantation
A newer treatment approach, non-myeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone marrow cells of the recipient. Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the "graft versus tumor" effect to resist the inherent increased risk of cancer relapse. Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants. This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space.
Transplant rejection
Initiated by preexisting humoral immunity, "hyperacute rejection" manifests within minutes after transplant, and if tissue is left implanted brings systemic inflammatory response syndrome. Of high risk in kidney transplants is rapid clumping, namely agglutination, of red blood cells (RBCs or erythrocytes), as an antibody molecule binds multiple target cells at once.
Transplant glomerulopathy
Transplant glomerulopathy, abbreviated TG, is a disease of the glomeruli in transplanted kidneys. It is a type of renal injury often associated with chronic antibody-mediated rejection. However, transplant glomerulopathy is not specific for chronic antibody-mediated rejection; it may be the result of a number of disease processes affecting the glomerular endothelium.
Management of Crohn's disease
Small intestine transplants are becoming less experimental, but are still mainly performed in response to short bowel syndrome due to a high rate of transplant rejection.
Frank Macfarlane Burnet
However, later studies showed that cells or tissues transplanted before the immune system development of the recipient, such as in embryonic recipients, could be treated as foreign and trigger rejection, countering Burnet's explanation for self tolerance. In contrast to the Burnet hypothesis of a special tolerance-inducing period defined by the age of the animal, Joshua Lederberg proposed in 1959, that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance-sensitive. Lederberg's concept is now known as central tolerance, and is widely accepted. It may also explain the success of some transplants given early in life and the failure to induce tolerance in other studies. Burnet noted that his contributions to immune tolerance were strictly theoretical:
My part in the discovery of acquired immunological tolerance was a very minor one—it was the formulation of an hypothesis that called for experiment.
Immune tolerance in pregnancy
Many cases of spontaneous abortion may be described in the same way as maternal transplant rejection, and a chronic insufficient tolerance may cause infertility. Other examples of insufficient immune tolerance in pregnancy are Rh disease and pre-eclampsia:Pregnancies resulting from egg donation, where the carrier is less genetically similar to the fetus than a biological mother, are associated with a higher incidence of pregnancy-induced hypertension and placental pathology. The local and systemic immunologic changes are also more pronounced than in normal pregnancies, so it has been suggested that the higher frequency of some conditions in egg donation may be caused by reduced immune tolerance from the mother.
Xenotransplantation
Also known as delayed xenoactive rejection, this type of rejection occurs in discordant xenografts within 2 to 3 days, if hyperacute rejection is prevented. The process is much more complex than hyperacute rejection and is currently not completely understood. Acute vascular rejection requires de novo protein synthesis and is driven by interactions between the graft endothelial cells and host antibodies, macrophages, and platelets. The response is characterized by an inflammatory infiltrate of mostly macrophages and natural killer cells (with small numbers of T cells), intravascular thrombosis, and fibrinoid necrosis of vessel walls.
Michael Woodruff
After passing his exam, Woodruff entered his position at Sheffield, where he trained in emergency and elective surgery. Originally, he had planned to do surgical research, but Sheffield had no space for him in its surgical lab. Instead, Woodruff was given a place in the pathology laboratory where he studied transplant rejection, a process in which the immune system of a transplant recipient attacks the transplanted tissue. Woodruff was particularly interested in thyroid allografts to the anterior chamber of the eye because they did not appear to meet with rejection. Woodruff's work with the allografts gave him a solid basis to work in the developing field of transplantion and rejection. To further himself in these areas, Woodruff arranged to meet Peter Medawar, an eminent zoologist and important pioneer in the study of rejection. The two men discussed transplantation and rejection, beginning a lasting professional relationship. Despite his achievements at Sheffield, Woodruff was rejected upon applying for a post at the Royal Melbourne Hospital.
Domestic pig
To date, no xenotransplantation trials have been entirely successful due to obstacles arising from the response of the recipient’s immune system—generally more extreme than in allotransplantations, ultimately results in rejection of the xenograft, and in some cases result in the death of the recipient—including hyperacute rejection, acute vascular rejection, cellular rejection and chronic rejection. An early major breakthrough was the 1,3 galactosyl transferase gene knockout.
Organ transplantation
Organ donors may be living, brain dead, or dead via circulatory death. Tissue may be recovered from donors who die of circulatory death, as well as of brain death – up to 24 hours past the cessation of heartbeat. Unlike organs, most tissues (with the exception of corneas) can be preserved and stored for up to five years, meaning they can be "banked". Transplantation raises a number of bioethical issues, including the definition of death, when and how consent should be given for an organ to be transplanted, and payment for organs for transplantation. Other ethical issues include transplantation tourism (medical tourism) and more broadly the socio-economic context in which organ procurement or transplantation may occur. A particular problem is organ trafficking. There is also the ethical issue of not holding out false hope to patients.
Organ transplantation
Recently, researchers have been looking into means of reducing the general burden of immunosuppression. Common approaches include avoidance of steroids, reduced exposure to calcineurin inhibitors, and other means of weaning drugs based on patient outcome and function. While short-term outcomes appear promising, long-term outcomes are still unknown, and in general, reduced immunosuppression increases the risk of rejection and decreases the risk of infection. The risk of early rejection is increased if corticosteroid immunosuppression are avoided or withdrawn after renal transplantation.
Organ transplantation
As the rising success rate of transplants and modern immunosuppression make transplants more common, the need for more organs has become critical. Transplants from living donors, especially relatives, have become increasingly common. Additionally, there is substantive research into xenotransplantation, or transgenic organs; although these forms of transplant are not yet being used in humans, clinical trials involving the use of specific cell types have been conducted with promising results, such as using porcine islets of Langerhans to treat type 1 diabetes. However, there are still many problems that would need to be solved before they would be feasible options in people requiring transplants.
Hematopoietic stem cell transplantation
Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed (myeloablation). Prior to the administration of new cells (engraftment) patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics. However, antiviral medications, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic infection in seropositive patients. The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.
Destination therapy
Destination therapy is a therapy that is final rather than being a transitional stage until another therapy—thus, in transportation metaphor, a destination in itself rather than merely a bridge or road to the destination. The term usually refers to ventricular assist devices or mechanical circulatory support to keep the existing heart going, not just until a heart transplant can occur, but for the rest of the patient's life expectancy. It is thus a course of treatment for severe (e.g., NYHA class IV/ACC stage D) heart failure patients who are not likely candidates for transplant. In contrast, bridge-to-transplant therapy is a way to stay alive long enough, and stay healthy enough, to await transplant while maintaining eligibility for transplant.
ABO-incompatible transplantation
ABO-incompatible (ABOi) transplantation is a method of allocation in organ transplantation that permits more efficient use of available organs regardless of ABO blood type, which would otherwise be unavailable due to hyperacute rejection. Primarily in use in infants and young toddlers, research is ongoing to allow for increased use of this capability in adult transplants. Normal ABO-compatibility rules may be observed for all recipients. This means that anyone may receive a transplant of a type-O organ, and consequently, type-O recipients are one of the biggest beneficiaries of ABO-incompatible transplants. While focus has been on infant heart transplants, the principles generally apply to other forms of solid organ transplantation.
Transplantable organs and tissues
Ovary transplantation, giving rise to successful pregnancies, has so far only been carried out on identical twins, and will result in children who will have the genetic inheritance of the organ donor and not the recipient. More importantly, use of an ovarian transplant from a genetically identical donor prevents rejection of the donated organ. This bypasses the need for immune suppressants to maintain the function of the donated ovary, which is not vital for survival. More significantly, many immunosuppressants, such as mycophenolate mofetil, may cause birth defects.
Carlos Manuel Chávez
Only a few anti-rejection medicines were available to doctors at that time. The doctors surmised the heart may have been too small and that the patient too weak before surgery for the transplant to take place.
Lung transplantation
In order to prevent transplant rejection and subsequent damage to the new lung or lungs, patients must take a regimen of immunosuppressive drugs. Patients will normally have to take a combination of these medicines in order to combat the risk of rejection. This is a lifelong commitment, and must be strictly adhered to. The immunosuppressive regimen is begun just before or after surgery. Usually the regimen includes ciclosporin, azathioprine and corticosteroids, but as episodes of rejection may reoccur throughout a patient's life, the exact choices and dosages of immunosuppressants may have to be modified over time. Sometimes tacrolimus is given instead of ciclosporin and mycophenolate mofetil instead of azathioprine.
Kidney transplantation
Transplant recipients must take immunosuppressive anti-rejection drugs for as long as the transplanted kidney functions. The routine immunosuppressives are tacrolimus (Prograf), mycophenolate (Cellcept), and prednisolone; these drugs cost US$1,500 per month. In 1999 the United States Congress passed a law that restricts Medicare from paying for more than three years for these drugs, unless the patient is otherwise Medicare-eligible. Transplant programs may not transplant a patient unless the patient has a reasonable plan to pay for medication after the Medicare expires; however, patients are almost never turned down for financial reasons alone. Half of end-stage renal disease patients only have Medicare coverage.
Transplant surgeon
Sometimes, the separation of conjoined individuals requires transplantation of an organ or organs, especially if complications develop. End-stage renal disease (stages 5 and 6; either acute and non-reversible, or chronic), severe congestive or other heart failure or certain congenital cardiac structural defects (where the blood cannot be oxygenated or backflows, or where the ejection fraction or distribution of blood is insufficient); and advanced chronic obstructive pulmonary disease, cystic fibrosis (when the lungs are no longer able to function), or emphysema, are possible indicators for, respectively, renal (kidney), cardiac (heart), or pulmonary (lung) transplantation.
Passenger leukocyte
In tissue and organ transplantation, the passenger leukocyte theory is the proposition that leucocytes within a transplanted allograft sensitize the recipient's alloreactive T-lymphocytes, causing transplant rejection.
Graft-versus-host disease
White blood cells of the donor's immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the recipient's body's cells, which leads to GvHD. This should not be confused with a transplant rejection, which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor's immune system's white blood cells reject the recipient. The underlying principle (alloimmunity) is the same, but the details and course may differ. GvHD can also occur after a blood transfusion if the blood products used have not been irradiated or treated with an approved pathogen reduction system.
Xenotransplantation
The Ethics Committee of the International Xenotransplantation Association points out one major ethical issue is the societal response to such a procedure. The assumption is that the recipient of the transplantation will be asked to undergo lifelong monitoring, which would deny the recipient the ability to terminate the monitoring at any time, which is in direct opposition of the Declaration of Helsinki and the US Code of Federal Regulations.
In 2007, xenotransplantation was banned under ethical grounds in all countries but Argentina, Russia and New Zealand. Since then, the practice has only been carried out to treatment for diabetes type 1 to serve as a substitute for penicillin injections.
Philadelphia chromosome
Cord blood transplant is favored by some when a 10/10 bone marrow match is not available, and cord blood transplant may have some advantages, including a reduced incidence of graft-vs-host disease (GVHD), which is a common and significant complication of transplant. However, transplant with cord blood sometimes requires longer periods of time for engraftment, which may increase the potential for complications due to infection. Regardless of the type of transplant, transplant-related mortality and relapse are possible, and the rates may change as treatment protocols improve. For second remission (CR2), if achieved, both chemotherapy and transplant options are possible, and many physicians prefer transplant.
Xenotransplantation
The Food and Drug Administration (FDA) has also stated that if a transplantation takes place the recipient must undergo monitoring for the rest of that recipient's lifetime and waive their right to withdraw. The reason for requiring lifelong monitoring is due to the risk of acute infections that may occur. The FDA suggests that a passive screening program should be implemented and should extend for the life of the recipient.
Philip Caves
However, by being able to examine small biopsies taken from the interventricular septum of the heart it was possible to detect early histological changes of rejection and increase immunosuppressive treatment earlier and more effectively. Likewise, repeat biopsy after some days could define whether the rejection was resolving and reduce therapy sooner. The device, a modification of one produced by Konno in Japan, was inserted through the right internal jugular vein and guided into the right ventricle of the transplanted heart. A biopsy was then taken. This technique of allowing early detection of acute organ rejection and confirming absence of rejection eventually resulted in the establishment of a heart rejection grading system. Cyclosporin was given if the biopsy result indicated early rejection. By the 1980s this was considered the best method of detection. During his second year, Stanford's leading cardiothoracic surgeon, Norman Shumway had become impressed with what Caves had achieved and he promoted Caves to Chief Resident in 1972 and to Staff Surgeon in charge of the Transplant programme in 1973.
RNA transfection
Long-RNA transfection is the process of deliberately introducing RNA molecules longer than about 25nt into living cells. A distinction is made between short- and long-RNA transfection because exogenous long RNA molecules elicit an innate immune response in cells that can cause a variety of nonspecific effects including translation block, cell-cycle arrest, and apoptosis.
Xenotransplantation
Chronic rejection is slow and progressive, and usually occurs in transplants that survive the initial rejection phases. Scientists are still unclear how chronic rejection exactly works, research in this area is difficult since xenografts rarely survive past the initial acute rejection phases. Nonetheless, it is known that XNAs and the complement system are not primarily involved. Fibrosis in the xenograft occurs as a result of immune reactions, cytokines (which stimulate fibroblasts), or healing (following cellular necrosis in acute rejection). Perhaps the major cause of chronic rejection is arteriosclerosis. Lymphocytes, which were previously activated by antigens in the vessel wall of the graft, activate macrophages to secrete smooth muscle growth factors. This results in a build up of smooth muscle cells on the vessel walls, causing the hardening and narrowing of vessels within the graft. Chronic rejection leads to pathologic changes of the organ, and is why transplants must be replaced after so many years. It is also anticipated that chronic rejection will be more aggressive in xenotransplants as opposed to allotransplants.
History and naming of human leukocyte antigens
Historical perspective is important to an understanding of how the HLA were systematized. In organ transplant the goal was to explain graft rejection for recipients, and of course, to prevent future rejection. From this perspective, the cause of rejections were found to be "antigens". In the same way bacterial antigens can cause inflammatory response, HLA antigens from the donor of the organ caused an inflammatory response when placed in a recipient. This is called allograft [allo = different, graft(medical) = transplant] rejection.
Transplantable organs and tissues
The recipient of a hand transplant needs to take immunosuppressive drugs, as the body's natural immune system will try to reject, or destroy, the hand. These drugs cause the recipient to have a weak immune system and suffer severely even from minor infections.
Xenotransplantation
This rapid and violent type of rejection occurs within minutes to hours from the time of the transplant. It is mediated by the binding of XNAs (xenoreactive natural antibodies) to the donor endothelium, causing activation of the human complement system, which results in endothelial damage, inflammation, thrombosis and necrosis of the transplant. XNAs are first produced and begin circulating in the blood in neonates, after colonization of the bowel by bacteria with galactose moieties on their cell walls. Most of these antibodies are the IgM class, but also include IgG, and IgA.
Organ transplantation
Until recently, people labeled as obese were not considered appropriate candidates for renal transplantation. In 2009, the physicians at the University of Illinois Medical Center performed the first robotic renal transplantation in an obese recipient and have continued to transplant people with Body Mass Index (BMI)’s over 35 using robotic surgery. As of January 2014, over 100 people that would otherwise be turned down because of their weight have successfully been transplanted.
Organ donors may be living or may have died of brain death or circulatory death. Most deceased donors are those who have been pronounced brain dead. Brain dead means the cessation of brain function, typically after receiving an injury (either traumatic or pathological) to the brain, or otherwise cutting off blood circulation to the brain (drowning, suffocation, etc.). Breathing is maintained via artificial sources, which, in turn, maintains heartbeat. Once brain death has been declared the person can be considered for organ donation. Criteria for brain death vary. Because less than 3% of all deaths in the U.S. are the result of brain death, the overwhelming majority of deaths are ineligible for organ donation, resulting in severe shortages.
Organ transplantation in Israel
Yaakov Levi, the director of the Heart Transplant Unit at Sheba Medical Center has called for organs to be allocated first to those who are willing to donate their own organs and have possessed a donor card for several years. This call was accepted and incorporated into the 2008 law. According to the New York Times, "Organ donation rates in Israel are among the lowest in the developed world, about one-third the rate in Western Europe, in large part because of what Health Ministry officials and doctors describe as a widespread impression that Jewish law prohibits transplants as a 'desecration of the body...'"
Liver transplantation
Historically, HIV was considered an "absolute" contraindication to liver transplantation. This was in part due to concern that the infection would be worsened by the immunosuppressive medication which is required after transplantation.
Transplant rejection
Developed through an earlier "primary exposure" that primed specific immunity to the "nonself" antigen, a transplant recipient can have specific antibody crossreacting with the donor tissue upon the transplant event, a "secondary exposure". This is typical of minor blood group exposure (e.g. Kell) following allogenic blood transfusion or trauma during pregnancy. At secondary exposure, these crossreactive antibody molecules interact with aspects of innate immunity—soluble immune proteins called complement and innate immune cells called phagocytes—which inflames and destroys the transplanted tissue.
Heart failure
In select cases, heart transplantation can be considered. While this may resolve the problems associated with heart failure, the person must generally remain on an immunosuppressive regimen to prevent rejection, which has its own significant downsides. A major limitation of this treatment option is the scarcity of hearts available for transplantation.
Transgender rights in the United States
Transgender people who haven't undergone sex reassignment surgery are still able to procreate. However, many states mandate sex reassignment surgery in order for a trans person's gender identity to be legally recognized. This has been criticized as forcible sterilization. Some transgender people wish to retain their ability to procreate. Others do not require hysterectomy, phalloplasty, metoidioplasty, penectomy, orchiectomy, or vaginoplasty to treat their gender dysphoria. In these cases, the sexual reassignment surgery is considered medically unnecessary. Furthermore, sexual reassignment surgery is generally the final medical procedure in a complete sex change, and is a procedure which many trans people find financially prohibitive.
Organ transplantation
A transplant of organs or tissue from one species to another. An example is porcine heart valve transplant, which is quite common and successful. Another example is attempted piscine-primate (fish to non-human primate) transplant of islet (i.e. pancreatic or insular tissue) tissue. The latter research study was intended to pave the way for potential human use if successful. However, xenotransplantion is often an extremely dangerous type of transplant because of the increased risk of non-compatibility, rejection, and disease carried in the tissue. In an opposite twist, Ganogen Research Institute CEO Eugene Gu is studying how to transplant human fetal hearts and kidneys into animals for future transplantation into human patients to address the shortage of donor organs.
Intestine transplantation
There are three major types of intestine transplants: an isolated intestinal graft, a combined intestinal-liver graft, and a multivisceral graft in which other abdominal organs may be transplanted as well. In the most basic and common graft, an isolated intestinal graft, only sections of the jejunum and ileum are transplanted. These are performed in the absence of liver failure. In the event of severe liver dysfunction due to PN, enzyme deficiencies, or other underlying factors, the liver may be transplanted along with the intestine. In a multivisceral graft, the stomach, duodenum, pancreas, and/or colon may be included in the graft. Multivisceral grafts are considered when the underlying condition significantly compromises other sections of the digestive system, such as intra-abdominal tumors that have not yet metastasized, extensive venous thrombosis or arterial ischemia of the mesentery, and motility syndromes.