CONDITIONED UNRESPONSIVENESS IN ORGAN TRANSPLANTATION

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We propose to employ a molecular approach to develop effective strategies for inducing specific immunologic unresponsiveness at the level of a transplanted organ allograft. This is based on recent evidence that aberrant signal transduction arising from inappropriate antigen presentation affects binding of nuclear regulatory factors to promoter regions of lymphokine genes and probably others to cause lymphocyte inactivation &/or reprogramming, and a growing body of evidence that limiting numbers T lymphocytes which have undergone such a functional switch serve to modulate alloimmune responses within the microenvironnent of a graft. Specific Aim 1 defines heterogeneity of antigen receptors expressed by infiltrating T cells for defined epitopes borne by the graft. Specific Aim 2 addresses the susceptibility of functional and phenotypically distinguishable T cell clones to inactivation/reprogramming. Specific Aim 3 defines molecular correlates of lymphocytes activation in states of graft rejection and conditioned unresponsiveness. Specific Aim 4 tests the thesis that of an oligoclonal population of T lymphocytes which have undergone a functional switch are driven by antigen to run an alternate program and serve to generate a state of conditioned unresponsiveness within the microenvironment of the graft which permits long term survival of the organ. An analysis of the determinants of conditioned unresponsiveness at the level of the organ allograft may permit new strategies for modulating the (allo)immune response in clinical transplantation and autoimmune disease to be developed.