Adaptive immune responses are directed by specific recognition of antigen but are also driven by general contextual signs of injury. Organ transplantation provides both of these conditions: substantial amounts of alloantigen and significant injury through donor brain death, ischemia reperfusion and the procedure of surgery. The precise role of injury in the evolution of an alloimmune response has not been well defined; there is a general assumption that injury augments alloimmunity. To understand the relationship between alloimmunity and injury we used a murine model of controlled cell necrosis in the context of alloantigen exposure. Skeletal muscle tissue from C57BL/6 mice was subjected to mechanical and/or thermal necrosis. Standardized amounts of necrotic debris were subsequently injected subcutaneously into naive C57BL/6 mice with and without alloantigen, and cellular and humoral alloimmunity was assessed. Consistent with our expectations, injection of necrotic debris produced a local and transient immune reaction, with increased T cell activation evidenced by enhanced expression of CD44 (p<0.001) and LFA-1 (p<0.05) in the draining lymph nodes 3 days after the insult. An acute increase in the effector memory population (CD44Hi CD62Llo) was also seen. Surprisingly, however, when alloantigen (BALB/c splenocytes) was combined with necrotic tissue there was no differential T cell activation or maturation. Alloresponses ensued in both settings (day10), the proportion of Foxp3+ regulatory T cells and the expression of antigen presenting cell markers CD80/CD86 for both the groups were same. Similarly, alloantibody levels for the group with combined stimuli were not different compared to the alloantigen alone group. In the presence of immunosuppression with CTLA4-Ig alloimmunity was observed but necrotic tissue did not alter T cell activation or maturation. Mechanical necrosis alone (without thermal injury) brought about greater and more sustained activation of T cells, suggesting that some elements of the response to injury are protein-derived and subject to denaturation. We found that molecular signals of tissue injury induced by thermal and mechanical cell necrosis produced a local transient cellular response, but this response did not differentially alter the maturation or activation of T cells, influence the size and effectiveness of the allospecific T cell repertoire, or augment alloantibody responses. While the role of injury in alloimmunity is postulated, empiric evidence for a substantial effect is lacking.

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