Abstract
Recent evidences indicate an important role of tissue inflammatory responses by innate immune cells in allograft acceptance and survival. Here we investigated the role of mast cells (MC) in an acute male to female skin allograft rejection model using red MC and basophil (RMB) mice enabling conditional MC depletion. Kinetic analysis showed that MCs markedly accelerate skin rejection. They induced an early inflammatory response through degranulation and boosted local synthesis of KC, MIP-2, and TNF. This enhanced early neutrophil infiltration compared to a female-female graft-associated repair response. The uncontrolled neutrophil influx accelerated rejection as antibody-mediated depletion of neutrophils delayed skin rejection. Administration of cromolyn, a MC stabilizer and to a lesser extent ketotifen, a histamine type I receptor antagonist, and absence of MCPT4 chymase also delayed graft rejection. Together our data indicate that mediators contained in secretory granules of MC promote an inflammatory response with enhanced neutrophil infiltration that accelerate graft rejection.
Highlights
Many chronic diseases have in common severe tissue destruction with solid organ or tissue transplantation often representing the unique solution to avoid end stage organ failure [1]
We initially verified the efficient depletion of tdT-positive mast cells (MC) in the skin after systemic and local injections starting 12 days before the intended surgery according to the protocol depicted in Figure 1A to allow basophils replenishment
Follow-up quantification using confocal imaging confirmed that MCs remain substantially depleted up to D11 (
Summary
Many chronic diseases have in common severe tissue destruction with solid organ or tissue transplantation often representing the unique solution to avoid end stage organ failure [1]. Transplantation is possible for many organs (heart, lung, liver, pancreas, kidneys) and tissues (skin, heart valves, cornea etc) enabled by the use of potent immunosuppressive drugs to maintain immunological tolerance [2] They are associated with severe side effects increasing tumor incidence, susceptibility to infections, and chronic graft inflammatory processes. While T cell- and Antibody (Ab)-mediated rejection mechanisms have been known for long as the prime actors [3], new evidences show that tissue inflammatory responses as well as the immunological environment including NK cells, dendritic cells, monocytes/macrophages, neutrophils, and eosinophils can importantly impact allograft acceptance and/or destabilize an established tolerant state [4,5,6,7] These findings of high clinical relevance advocate for novel strategies to minimize local inflammation in engrafted tissues.
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