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Spring 1994Volume 1, Number 1 |
During the past two decades, the use of immunosuppressive drugs in transplantation has revolutionized our ability to treat transplant rejection and other immune disorders. As a result, well over 80% of kidney allograft recipients currently maintain their allografts for over one year. However, the ultimate goal — permanent transplantation tolerance — has not yet been achieved. Patients who are treated with cyclosporin A, steroids, monoclonal antibodies or other therapies must continue immunosuppressive therapy throughout their lives, increasing their risk of infectious disease, cancer, and immunodeficiency. On rare occasions, however, individuals who discontinue immunosuppressive drugs retain their transplanted tissue indefinitely. In these cases the immune system adapts to foreign tissue and allows permanent engraftment of the organ.
Major advances have occurred in our understanding of the basic biology of immune recognition of foreign antigens. By understanding the fundamental nature of immune activation, we can begin to develop a new generation of immunosuppressive agents for transplantation.
Co-Stimulation and T-Cell Anergy
Among the most exciting developments in T cell biology has been the understanding of co-stimulation as it relates to T-cell activation and tolerance. Over 20 years ago Bretcher and Cohn postulated that immune activation of lymphocytes required two signals, one delivered through the antigen-specific T- (or B-) cell receptor and the other via a cell/cell interaction of other cell surface molecules. Transplantation experiments supported this hypothesis by demonstrating that antigens expressed on non-conventional antigen-presenting cells were unable to induce immune responses in vivo. More recently, these studies have been extended using transgenic mice expressing major histocompatibility complex (MHC) antigens in a tissue-specific fashion. T cells isolated from mice expressing a class I or class II allogeneic MHC antigen on only pancreatic islet cells not only failed to respond to the foreign tissue, but the tissue-specific T cells were inactivated in these animals.
More recently, T-cell inactivation, termed "anergy," was demonstrated in T-cell clones in vitro. Jenkins, Schwartz and colleagues demonstrated that when T cell clones encounter an antigen-specific signal delivered by the MHC/antigen complex interacting with the T-cell receptor, early biochemical and molecular changes are induced in the T cells. Complete cellular activation, however, depends on a second receptor/ligand-mediated signal, defined as co-stimulation. In fact, in the absence of effective co-stimulation, the T cells become anergic, as assessed by their failure to proliferate and produce lymphokines (IL-2).
One of the best characterized T-cell co-stimulatory molecules is CD28. CD28 is constitutively expressed on naive T cells, and its engagement during T-cell activation is required for IL-2 production and subsequent T-cell proliferation. Unlike other T-cell activation/adhesion molecules, CD28 mediates signalling that is T-cell receptor-independent and cyclosporin A resistant. Several years ago, Linsley and colleagues demonstrated that B7-1(B7), a cell surface molecule expressed on dendritic cells and activated B cells, was a ligand for CD28, capable of co-stimulating T-cell responses. Furthermore, blocking the CD28 signalling pathway not only inhibited T-cell proliferation but, in a subset of T-cell clones, induced a state of antigen-specific anergy. Recently, additional B7 family members have been identified (B7-2 and B7-3) that also participate in T-cell co-stimulation. In fact, B7-2 appears to be the major co-stimulatory molecule in the transplant setting. The physiologic importance of this signalling pathway has recently been demonstrated in vivo using a soluble CD28 antagonist, CTLA4Ig, which is derived from a CD28 homologue, CTLA-4; the latter is expressed on activated T cells. Human CTLA4Ig inhibits T-cell proliferation in vitro and suppresses a variety of immunological responses including allogeneic graft rejection and antibody production. In a xenogeneic islet transplant model, CTLA4Ig therapy induced donor-specific tolerance.
Thus, blocking the interaction among CD28, B, and B7 family molecules provides, perhaps for the first time, the means to selectively inactivate only those T cells that respond to the graft without affecting the rest of the immune system. Future studies will examine the use of co-stimulation antagonists in large animal models and human beings.
Jeffrey Bluestone, PhD
University of Chicago
Chicago, Illinois
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