Blockade of T cell costimulation

Additional T cell signals (termed costimulation), other than those delivered by CD3/TCR complex stimulation, are required to drive T cell expansion. A state of nonresponsiveness termed anergy is induced in T cells that have received signaling via their CD3/TCR complex in the absence of adequate costimulation. T Cells not receiving CD3/TCR complex signaling are unaffected. In theory, GVHD can be inhibited by temporarily precluding T cell costimulation during initial alloantigen exposure, leaving intact the majority of T cells to mediate leukemia- and viral-specific T cell responses upon antigen exposure later in the post-BMT course. Costimulator molecules include members of the immunoglobulin supergene family (e.g. CD28.-B7), tumor necrosis factor/nerve growth factor receptor families (e.g. CD40 ligand: CD40, 4-lBB:4-lBB ligand; 0X40:0X40 ligand), and adhesion molecules (e.g. LFA-1:ICAM-1, CD2:CD48). Balancing these positive signals are negative regulators which downregul-ate immune responses primarily by inducing cell death, compete for the same substrates as the positive regulators, or provide negative regulatory signals. The net balance of positive and negative regulators of T cell activation and expansion determine whether donor alloreactive T cells can reach the critical threshold number and stage of activation neces sary to cause GVHD lethality in a recipient. As an example of the requirement for costimulation, the CD28/B7 pathway, the most well-studied interaction, will be highlighted. CD28 is constitutivelv expressed on all murine T cells and its natural ligands, B7-1 or B7-2, are predominantly found on activated antigen-presenting cells. The infusion of CTLA4-Ig, a protein consisting of the high avidity B7 ligand-binding extracellular domain of CTLA-4 fused to the C71 moiety of immunoglobulin, has been noted to suppress sheep red blood cell responses, xenogeneic islet cell and cardiac allograft rejection, immune responses to self antigens, and GVHD responses. The infusion of anti-B7 mAbs post-BMT allowed survival rates of ^94% in allogeneic recipients of either CD4+ or CD8~ T cells, in contrast to no survival of controls. In a human mixed lymphocyte reaction (MLR) system, blockade of CD28/B7 interaction was found to induce donor antihost alloantigen specific hyporesponsiveness. Thus, it may be possible to render donor T cells anergic to allo-antigens in vitro prior to in vivo transfer into BMT recipients.

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