The composition of the microbiota modulates allograft rejection

Impact of environmental factors on alloimmunity and transplant fate

“…Using a murine skin transplantation model, Lei et al showed that pretreatment with broad-spectrum antibiotics (Abx) or use of germ-free mice resulted in prolonged allograft survival (142). Mechanistically, Abx pretreatment was associated with a diminished APC capacity to activate alloreactive T cells, resulting in reduced intragraft T cell infiltration.…”

“…However, the benefit of this approach has been challenged with the demonstration that loss of microbiota diversity is associated with increased lethality in adult BMT (152). Although Abx pretreatment reduced alloimmunity and promoted solid graft survival in mice (142), a more precise understanding of the specific bacteria that promote rejection, and perhaps identification of bacteria that antagonize rejection and that one may want to retain or repopulate after transplantation, are needed. Also, because some bacteria depend on one another for survival (153) or antagonize one another (154), even narrow-spectrum Abx may have unintended consequences that will need to be studied.…”

Micromanaging alloimmunity

“…All of these investigations have focused on the role of pathogenic organisms in the augmentation of alloimmunity and precipitation of allograft rejection, while the impact of nonpathogenic, commensal organisms on the generation and nature of alloimmune responses has remained relatively unknown. Now, in this issue, Lei and colleagues report that the intestinal microbiome potently influences the magnitude of the alloreactive T cell response and accelerates allograft rejection in murine models of transplantation (9).…”

“…Lei et al addressed this discrepancy by asking an elegantly simple question: does the presence of normal, commensal microbiota at the time of transplantation alter the kinetics of allograft rejection? Working in a model of minor antigen disparity (H-Y), Lei and colleagues interrogated the kinetics of skin graft rejection in germ-free (GF) animals relative to specific pathogen-free (SPF) control mice and showed that rejection was markedly delayed in animals lacking commensal microbiota (9). Further, fecal transplant from SPF mice into GF animals restored the accelerated rejection kinetics, demonstrating that microbial colonization is sufficient to enhance the rigor of the alloimmune response.…”

“…An important point is that, in addition to restoring intestinal microbiota, oral gavage of fecal contents into GF mice was also sufficient to restore microbial colonization of the skin (9). Because Lei and colleagues were working in a skin transplant model, it was initially unclear whether the ability of microbiome reconstitution to accelerate skin allograft rejection was the result of systemic alteration of immunity or due to a local effect at the site of the graft.…”