A multitude of recent studies have demonstrated that the intestinal microbiota influences systemic autoimmunity and immune responses to infection. Organs associated with commensal bacteria, including skin, intestine, and lung, are notoriously difficult to tolerize following transplantation but whether this is due to microbiota-mediated signals facilitating acute rejection is not known. We hypothesize that commensal bacteria, either in the intestine or at the site of the graft, may normally promote the rejection of skin grafts. Our group and others have previously shown that when donor and recipient mice are globally deficient in MyD88-dependent Toll-like receptor (TLR) signaling, both minor mismatched skin allografts or major mismatched skin grafts in recipients treated with costimulation blockade are accepted long-term. However, because both damage- and pathogen-associated molecular patterns can signal via MyD88, these experiments cannot distinguish the contribution of cellular stress versus microbial signals to allograft rejection. Our current study investigates more directly the role of microbiota in allograft rejection using complementary approaches, including antibiotic treatment of donor and recipient mice and use of germ-free animals. Our preliminary results show that altering the intestinal microbiota by oral antibiotic treatment attenuates rejection of male skin by female recipients. Additionally, antibiotic treatment affecting the skin and intestinal microbiota significantly slows rejection of major mismatched skin in the presence of costimulation blockade. We also found that minor mismatched skin allografts are rejected in a delayed fashion when donor and recipients are both germ-free, though this experiment also needs to be repeated. The longer skin allograft survival in antibiotic-treated versus germ-free mice suggests that some commensal bacteria may serve to downregulate the response to skin allografts, while others may be more proinflammatory. We plan to colonize germ-free mice with different defined skin or gut microbes to narrow down the contribution of different groups of bacteria to rejection. This study will be important in understanding the requirements for achieving transplantation tolerance, particularly in organs associated with microbial communities.

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