Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.
Introduction
In pig-to-baboon heart/artery patch transplantation models, adequate costimulation blockade prevents a T cell response. After heart transplantation, coagulation dysfunction (thrombocytopenia, reduced fibrinogen, increased D-dimer) and inflammation (increased C-reactive protein [CRP]) develop. We evaluated whether coagulation dysfunction and/or inflammation can be detected following pig artery patch transplantation.
Methods
Baboons received heart (n=8) or artery patch (n=16) transplants from genetically-engineered pigs, and a costimulation blockade-based regimen. Heart grafts functioned for 15–130d. Artery recipients were euthanized after 28–84d. Platelet counts, fibrinogen, D-dimer, and CRP were measured.
Results
Thrombocytopenia and reduced fibrinogen developed only in recipients of hearts not expressing a coagulation-regulatory protein (n=4), but not in other heart or patch recipients. However, in heart recipients (n=8), there were sustained increases in D-dimer (<0.5–1.9ug/mL [p<0.01]), and CRP (0.26–2.2mg/dL [p<0.01]). In recipients of artery patches, there were also sustained increases in D-dimer (<0.5–1.4ug/mL [p<0.01]), and CRP (0.26–1.5mg/dL [p<0.001]). An IL-6R antagonist suppressed the increase in CRP, but not D-dimer.
Conclusion
The pig artery patch model has proved valuable for determining immunosuppressive regimens that prevent sensitization to pig antigens. This model also provides information on the sustained systemic inflammation seen in xenograft recipients (SIXR). An IL-6R antagonist may help suppress this response.
Bony fish are among the first vertebrates to possess an innate and adaptive immune system. In these species, the kidney has a dual function: filtering solutes similar to mammals and acting as a lymphoid organ responsible for hematopoiesis and antigen processing. Recent studies have shown that the mammalian kidney has an extensive network of mononuclear phagocytes, whose function is not fully understood. Here, we employed two-photon intravital microscopy of fluorescent reporter mice to demonstrate that renal dendritic cells encase the microvasculature in the cortex, extend dendrites into the peritubular capillaries, and sample the blood for antigen. We utilized a mouse model of systemic bacterial infection as well as immune complexes to demonstrate antigen uptake by renal dendritic cells. As a consequence, renal dendritic cells mediated T-cell migration into the kidney in an antigen-dependent manner in the setting of bacterial infection. Thus, renal dendritic cells may be uniquely positioned to play an important role not only in surveillance of systemic infection but also in local infection and autoimmunity.
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