Fig. 13.16 Grafting of bone marrow can be used to correct immunodeficiencies caused by defects in lymphocyte maturation, but two problems can arise. First, if there are mature t cells in the bone marrow, they can attack cells of the host by recognizing their MHC antigens, causing graft-versus-host disease (top panel). this can be prevented by t-cell depletion of the donor bone marrow (center panel). Second, if the recipient has competent t cells, these can attack the bone marrow stem cells (bottom panel). this causes failure of the graft by the usual mechanism of transplant rejection (see Chapter 15).
There is also a danger that mature, postthymic T cells that contaminate donor HSCs prepared from the peripheral blood or bone marrow might recognize the host as foreign and attack it, causing graftversushost disease (GVHD) (Fig. 13.16, top panel). This can be overcome by depleting the donor graft of mature T cells. For immunodeficiency diseases other than SCID where there are residual T cells and NK cells in the recipient, some form of myeloablative treatment (destruction of the bone marrow, typically using cytotoxic drugs) is usually carried out before transplantation, both to generate space for engraftment of the transplanted HSCs and to minimize the threat of hostversusgraft disease (HVGD) (see Fig. 13.16, third panel). The intensity of the myeloablative regimen is dependent on the nature of the immunodeficiency. For diseases where persistence of the patient’s cells can be tolerated, engraftment of only a fraction of donor HSCs is sufficient for cure and nonmyeloablative chemotherapy may suffice prior to HSC transplantation. In other conditions such as XLP, which require complete elimination of the patient’s blood cells and full engraftment of donor cells, more intensive (myeloablative) chemotherapy may be required.
Because many specific gene defects that cause inherited immunodeficiencies have been identified, an alternative therapeutic approach is somatic gene therapy. This strategy involves the isolation of HSCs from the patient’s bone marrow or peripheral blood, introduction of a normal copy of the defective gene with the use of a viral vector, and reinfusion of the corrected stem cells into the patient. Initially, retroviral vectors were used for gene therapy trials, but were ceased due to severe complications in some patients. Although the genetic defect was corrected in patients with Xlinked SCID, CGD, and WAS who received this treatment, some patients developed leukemia due to insertion of the retrovirus within a protooncogene. The inability to control the site in the genome in which retrovirally encoded genes insert and the use of viral vectors with strong promoters that can transactivate neighboring genes is therefore problematic. More recently, the use of selfinactivating retroviral and lentiviral vectors for gene correction has shown promise as a means of avoiding this complication. Also, a technique for the generation of induced pluripotent stem cells (iPS cells) from a patient’s own somatic cells has been demonstrated. Forced expression of a set of transcription factors can reprogram somatic cells to become pluripotent progenitors that can give rise to HSCs. This approach offers the promise of ‘repairing’ specific defective genes in patientderived stem cells by gene targeting ex vivo before reinfusion, but is not yet established. Until better methods for introduction of corrected genes into selfrenewing stem cells are identified, allogeneic HSC transplantation will remain the mainstay of treatment for many primary immunodeficiencies.
13-18 Noninherited, secondary immunodeficiencies are major predisposing causes of infection and death.