SPECIFIC UNRESPONSIVENESS IN ORGAN TRANSPLANTATION

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This program project represents a concerted effort to explore promising new means for inducing specific immunological tolerance to transplanted allogeneic tissue. The working assumption is that more selective immunosuppressive therapy combined with antigen provided in a more tolerogenic form will induce states of lasting unresponsiveness, requiring little or no continuing therapy. Experimental work showing enhanced graft survival by pre-treatment with allogeneic cells has been partially reproduced in humans in the form of partial HLA matched blood transfusions. The preliminary animal work which forms the basis for part of this proposal shows that synthetic peptides representing the polymorphic regions of MHC molecules immunize when injected with adjuvant, but are quite tolerogenic when fed into the GI tract, or given intravenously. The effect is initiated by peptide presentation by recipient (self) MHC molecules and appears to be mediated by a state of active immunity involving subsets of cells which down-regulate DTH, MLR proliferation, and graft rejection. Project #1 will study the cellular response induced in recipients of HLA directed single blood transfusions, and utilize selected synthetic HLA class I and II peptides in vitro to study the immunogenicity and tolerogenic potential in different responder combination, leading to a rationale for clinical trials of feeding or IV dosing to desensitize or tolerize transplant candidates. Project #2 will use knowledge on functionally different subsets of T cells which bear markers representing alternative forms of expressed surface molecules to design means of selective inhibition or stimulation of T cell subsets. To some extent cyclosporine has selectivity which spares suppressor type cells, but a higher degree of selectivity is desirable. Since unique combination of cell surface molecules seem to define a subset, the technology of producing bifunctional hybrid monoclonal antibodies, along with new and highly efficient means of linking cell toxins to mAbs now make it possible to manipulate cellular immune responses in ways not previously possible. Project #3 will test separately, and in combination, MHC peptides and the new bifunctional mAbs in mouse and rhesus monkey models. The knowledge gained from these experiments should lead to novel clinical trials, and could also have implications for some autoimmune diseases.