We've reported major roles for autoimmunity to the alpha 1 (V) of collagen V [col(V)] in acute and chronic lung transplant rejection. Data from these studies led us to hypothesize that abnormal homotrimers of alpha 1(V) chains induce anti-col(V) autoimmunity and organ transplant rejection. To test the hypothesis, we investigated whether the autoimmune component of atherosclerosis involves anti-col(V) autoimmunity, based solely on the fact that alpha 1 (V) homotrimers are found in human atherosclerotic plaques. Here we demonstrate that atherosclerosis in humans and rodents is in fact associated with anti-col(V) autoimmunity, constituting an important proof-of-concept in support ofthe link between alpha 1(V) homotrimer formation and anti-col(V) autoimmunity. We propose studies to demonstrate that aberrent alpha 1(V) homotrimers are expressed in obliterative bronchiolitis (OB), which underlies chronic lung transplant rejection;and in cardiac allograft vasculopathy (CAV), an atherosclerosis-like rejection pathology in heart transplants. We will also use homologous recombination to conditionally induce expression of alpha 1(V) homotrimers in vivo in mouse adult lung epithelium, adult smooth muscle cells, and in ail adult tissues that normally express col(V) to directly test the roles of this aberrant form of col(V) in OB and CAV, upon lung and heart transplantation, respectively;and in atherosclerosis, upon crossing of alpha 1 (V) homotrimer-expressing mice with ApoE-null mice. Various types of immune challenges and adoptive transfers will further test the roles of alpha 1 (V) homotrimers in initiating anti-col(V) autoimmunity in these novel mouse model systems. We will also employ homologous recombination to generate mice in which alpha 1 (V) epitopes, found by peptide analysis to be the most recognized by anti-col(V) reactive T cells and antibodies, are removed from the alpha 1(V) gene in vivo, to test the true roles of such epitopes in OB, CAV, atherosclerosis and anti-col(V) autoimmunity. Finally, we propose a series of in vitro and in vivo experiments to test the concept of an "activated" alpha 1(V)- containing stroma that can enhance and perpetuate pathological states, including OB, CAV, atherosclerosis, and perhaps other pathologies as well, and how such a stroma affects cellular behaviors.
Work proposed here arises directly from our previous studies that provided insights into molecular mechanisms involved in lung transplant rejection. The proposed work has the potential to improve our understanding of molecular mechanisms that underlie lung and heart transplant rejection, atherosclerosis (a major killer in Western societies), and perhaps a number of other human diseases that involve autoimmunity.
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