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 rejecfion. To test the hypothesis, we invesfigated whether the autoimmune component of atherosclerosis involves anfi-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 anfi-col(V) autoimmunity, constituting an important proof-of-concept in support ofthe link between alpha 1(V) homotrimer formafion and anti-col(V) autoimmunity. We propose studies to demonstrate that aberrent alpha 1(V) homotrimers are expressed in obliterative bronchiolitis (OB), which underiies chronic lung transplant rejection;and in cardiac allograft vasculopathy (CAV), an atherosclerosis-like rejection pathology in heart transplants. We will also use homologous recombinafion to condifionally induce expression of alpha 1(V) homotrimers in vivo in mouse adult lung epithelium, adult smooth muscle cells, and in ali 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.

Public Health Relevance

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 underiie lung and heart transplant rejection, atherosclerosis (a major killer in Western sociefies), and perhaps a number of other human diseases that involve autoimmunity.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Indiana University-Purdue University at Indianapolis
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Muir, Alison M; Massoudi, Dawiyat; Nguyen, Ngon et al. (2016) BMP1-like proteinases are essential to the structure and wound healing of skin. Matrix Biol 56:114-131
Pandya, Pankita H; Fisher, Amanda J; Mickler, Elizabeth A et al. (2016) Hypoxia-Inducible Factor-1? Regulates CD55 in Airway Epithelium. Am J Respir Cell Mol Biol 55:889-898
Park, Arick C; Huang, Guorui; Jankowska-Gan, Ewa et al. (2016) Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance. J Biol Chem 291:3359-70
Agashe, Vrushali V; Burlingham, William J (2015) Autoimmune Reactivity in Graft Injury: Player or Bystander? Curr Transplant Rep 2:211-221
Wu, Qiang; Gupta, Pawan Kumar; Suzuki, Hidemi et al. (2015) CD4 T Cells but Not Th17 Cells Are Required for Mouse Lung Transplant Obliterative Bronchiolitis. Am J Transplant 15:1793-1804
Park, Arick C; Phillips, Charlotte L; Pfeiffer, Ferris M et al. (2015) Homozygosity and Heterozygosity for Null Col5a2 Alleles Produce Embryonic Lethality and a Novel Classic Ehlers-Danlos Syndrome-Related Phenotype. Am J Pathol 185:2000-11
Pandya, Pankita H; Wilkes, David S (2014) Complement system in lung disease. Am J Respir Cell Mol Biol 51:467-73
Shah, Rupal J; Emtiazjoo, Amir M; Diamond, Joshua M et al. (2014) Plasma complement levels are associated with primary graft dysfunction and mortality after lung transplantation. Am J Respir Crit Care Med 189:1564-7
Sullivan, J A; Jankowska-Gan, E; Shi, L et al. (2014) Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses. Am J Transplant 14:1512-22
Gracon, Adam S A; Wilkes, David S (2014) Lung transplantation: chronic allograft dysfunction and establishing immune tolerance. Hum Immunol 75:887-94

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