Antibodies specific for various physiological targets are being used, or are under investigation, to prevent the rejection of transplanted organs by inhibiting the development of harmful inflammatory and cytotoxic responses. For example, alemtuzumab, discussed in Section 16-4, is licensed for the treatment of certain leukemias but is also used in both solid-organ and bone marrow transplantation. In solid-organ transplantation, alemtuzumab may be given to the recipient around the time of transplantation to remove mature T lymphocytes from the circulation. In bone marrow transplantation, alemtuzumab can be used in vitro to deplete donor bone marrow of mature T cells before its infusion into a recipient, or used in vivo to treat the recipient following infusion. Elimination of mature T cells from donor bone marrow is very effective at reducing the incidence of graft-versus-host disease (see Section 15-36). In this disease, the T lymphocytes in the donor bone marrow recognize the recipient as foreign and mount a damaging response, causing rashes, diarrhea, and hepatitis, which can occasionally be fatal. Bone marrow transplantation is also used as a treatment for leukemia, as T cells in the graft can have a so-called graft-versus-leukemia effect where they recognize the leukemic cells as foreign and destroy them. It was originally thought that elimination of mature donor
Fig. 16.8 Monoclonal antibodies developed for immunotherapy.
A substantial fraction of pharmaceuticals currently under development are antibodies, and additions to this list, current as of this writing, are under development and in clinical trials.
T cells during such procedures would be disadvantageous, as the antileukemic action of the donor T cells could be lost, but this seems to not be the case when alemtuzumab is used as the depleting agent.
Specific antibodies directed against T cells have been used to treat episodes of graft rejection that occur after transplantation. The murine antibody muromomab (OKT3) targets the CD3 complex and leads to T-cell immunosuppression by inhibiting signaling through the T-cell receptor. It has been used clinically in solid-organ transplantation but is often associated with a dangerous side-effect, namely, the stimulation of pro-inflammatory cytokine release, and its use is declining. This cytokine release is related to muromomab’s intact
Fc region, which can activate Fc receptors via cross-linking and activate the cells that bear these receptors. In the antibody called teplizumab, or OKT3γ1 (Ala-Ala), amino acids 234 and 235 in the human IgG1 Fc region have been changed to alanines, and this antibody no longer stimulates cytokine release.
Two other antibodies, daclizumab and basiliximab, approved for treating kidney transplant rejection, are directed against CD25 (a subunit of the IL-2 receptor) and reduce T-cell activation, presumably by blocking the growth-promoting signals delivered by IL-2.
A primate model of kidney transplant rejection showed promising effects for a humanized monoclonal antibody against the CD40 ligand expressed by T cells (see Section 9-17). A possible mechanism of protection by this antibody is blockade of the activation of dendritic cells by helper T cells that recognize donor antigens. Only preliminary studies of anti-CD40 ligand antibodies have been performed in humans. One antibody was associated with thromboembolic complications and was withdrawn; a different anti-CD40 ligand antibody was administered to patients with the autoimmune disease systemic lupus erythematosus (SLE) without significant complications, but also with little evidence of efficacy.