Monoclonal Antibodies Can Suppress Graft Rejection Responses

Monoclonal antibodies directed against various surface molecules on cells of the immune system have been used successfully to suppress T-cell activity in general or to suppress the activity of subpopulations of T cells. Results from studies with animal models suggest further that certain monoclonals may be used to suppress only T cells that are activated. Successes with animal models and trials with humans give reason to believe that two types of strategies involving antibodies to suppress rejection will find broad clinical use. Monoclonal antibodies may be used to deplete the recipient of a certain broad or specific cell population; alternatively, they may be used to block co-stimulatory signals. In the latter case, a state of anergy is induced in those T cells that react to antigens present on the allograft.

A strategy to deplete immune cells involves use of a monoclonal antibody to the CD3 molecule of the TCR complex. Injection of such monoclonal antibodies results in a rapid depletion of 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 antibody. The cell with which the antibody reacts internalizes the toxin, causing its death. Another depletion strategy used to increase graft survival uses monoclonal antibodies specific for the high-affinity IL-2 receptor (anti-TAC). Since the high-affinity IL-2 receptor is expressed only on activated T cells, exposure to anti-TAC after the graft specifically blocks proliferation of T cells activated in response to the alloantigens of the graft.

Monoclonal-antibody therapy, which was initially employed to deplete T cells in graft recipients, also has been used to treat donors' bone marrow before it is transplanted. Such treatment is designed to deplete the immunocompetent T cells in the bone-marrow transplant; these are the cells that react with the recipient tissues, causing graft-versus-host disease (described below). Monoclonal antibodies with isotypes that activate the complement system are most effective in all cell-depletion strategies.

The CD3 receptor and the high-affinity IL-2 receptor are targets present on all activated T cells; molecules present on particular T-cell subpopulations may also be targeted for im-munosuppressive therapy. For example, a monoclonal antibody to CD4 has been shown to prolong graft survival. In one study, monkeys were given a single large dose of anti-CD4 just before they received a kidney transplant. Graft survival in the treated animals was markedly increased over that in untreated control animals. Interestingly, the anti-CD4 did not reduce the CD4+ T-cell count, but instead appeared to induce the T cells to enter an immunosuppressed state. This is an example of a nondepleting antibody.

Other targets for monoclonal-antibody therapy are the cell-surface adhesion molecules. Simultaneous treatment with monoclonal antibodies to the adhesion molecules ICAM-1 and LFA-1 for 6 days after transplantation has permitted indefinite survival of cardiac grafts between allogeneic mice. However, when either monoclonal antibody was administered alone, the cardiac transplant was rejected. The requirement that both monoclonal antibodies be given at the same time probably reflects redundancy of the adhesion molecules: LFA-1 is known to bind to ICAM-2 in addition to ICAM-1; and ICAM-1 is known to bind to Mac-1 and CD43 in addition to LFA-1. Only when all possible pairings among these adhesins are blocked at the same time is adhesion and signal transduction through this ligand pair blocked.

A practical difficulty with using monoclonal antibodies to prolong graft survival in humans is that they are generally of mouse origin. Many recipients develop an antibody response to the mouse monoclonal antibody, rapidly clearing it from the body. This limitation has been overcome by the construction of human monoclonal antibodies and mouse-human chimeric antibodies (see Figure 5-25 and Clinical Focus in Chapter 5).

Because cytokines appear to play an important role in allograft rejection, another strategy for prolonging graft survival is to inject animals with monoclonal antibodies specific for the implicated cytokines, particularly TNF-a, IFN-y, and IL-2. Monoclonal antibodies to TNF-a have been shown to prolong bone-marrow transplants in mice and to reduce the incidence of graft-versus-host disease. Monoclonal antibodies to IFN-y and to IL-2 have each been reported in some cases to prolong cardiac transplants in rats.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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