The ideal immunosuppressant would be antigen-specific, inhibiting the immune response to the alloantigens present in the graft (or vice versa alloantigens present in recipient in GVHD) while preserving the recipient's ability to respond to other foreign antigens. Although this goal has not yet been achieved, several more targeted immunosuppressive agents have been developed. Most involve the use of monoclonal antibodies (mAbs) or soluble ligands that bind specific cell-surface molecules. On limitation of most first-generation of mAbs came from their origin in animals. Recipients of these frequently developed an immune response to the nonhuman epitopes, rapidly clearing the mAbs from the body. This limitation has been overcome by the construction of humanized mAbs and mouse-human chimeric antibodies.
Many different mAbs have been tested in transplantation settings, and the majority work by either depleting the recipient of a particular cell population or by blocking a key step in immune signaling. Antithymocyte globulin (ATG), prepared from animals exposed to human lymphocytes, can be used to deplete lymphocytes in patients prior to transplantation, but has significant side effects. A more subset-specific strategy uses a mAb to the CD3 molecule of the TCR, called OKT3, and rapidly depletes mature T cells from the circulation. This depletion appears to be caused by binding of antibody-coated T cells to Fc receptors on phagocytic cells, which then phagocytose and clear the T cells from the circulation. In a further refinement of this strategy, a cytotoxic agent such as diphtheria toxin is coupled with the mAb. Antibody-bound cells then internalize the toxin and die. Another technique uses mAbs specific for the high-affinity IL-2 receptor CD25. Since this receptor is expressed only on activated T cells, this treatment specifically blocks proliferation of T cells activated in response to the alloantigens of the graft. However, since TREG cells also express CD25 and may aid in alloantigen tolerance, this strategy may have drawbacks. More recently, a mAb against CD20 has been used to deplete mature B cells and is aimed at suppressing AMR (antibody-mediated rejection) responses. Finally, in cases of bone marrow transplantation, mAbs against T-cell-specific markers have been used to pretreat the donor's bone marrow to destory immunocompetent T cells that may react with the recipient tissues, causing GVHD.
Because cytokines appear to play an important role in allograft rejection, these compounds can also be specifically targeted. Animal studies have explored the use of mAbs specific for the cytokines implicated in transplant rejection, particularly TNF-alpha, IFN-gamma, and IL-2. In mice, anti-TNF-alpha mAbs prolong bone marrow transplants and reduce the incidence of GVHD. Antibodies to IFN-gamma and to IL-2 have each been reported in some cases to prolong cardiac transplants in rats.
TH-cell activation requires a costimulatory signal in addition to the signal mediated by the TCR. The interaction between CD80/86 on the membrane of APCs and the CD28 or CTLA-4 molecule on T cells provides one such signal. Without this costimulatory signal, antigen-activated T cells become anergic. CD28 is expressed on both resting and activated T cells, while CTLA-4 is expressed only on activated T cells and binds CD80/86 with a 20-fold-higher affinity. In mice, D. J. Lenschow, J. A. Bluestone, and colleagues demonstrated prolonged graft survival by blocking CD80/86 signaling with a soluble fusion protein consisting of the extracellular domain of CTLA-4 fused to human IgG1 heavy chain. This new drug, belatacept, was shown to induce anergy in T cells directed against the graft tissue and has been approved by the FDA for prevention of organ rejection in adult kidney transplant pateints.