Gut Microbiota Can Impact Chronic Murine Lung Allograft Rejection

Vendor-specific microbiome controls both acute and chronic murine lung allograft rejection by altering CD4+Foxp3+ regulatory T cell levels

“…Contrary to established data demonstrating that antibiotic treatment leads to a uniform downregulation of both allo-and tumor-specific immunity, [6][7][8][9] we now demonstrate that in certain individuals dysbiosis can drastically alter pulmonary and systemic levels of CD4 + Foxp3 + regulatory T cells, thus increasing both acute and chronic rejection.…”

“…This was due to a prominent increase in inflammation of B10 grafts placed into B6E Maryland recipients where both cellular infiltration as well as rejection grade increased after antibiotics ( Figure 1A,B). These data further suggest that antibiotic-mediated alteration of the microbiome may not uniformly decrease the degree of the cellular immune response to allografts, as previously described, 6,7 but may be context, recipient, and facility dependent. Taken together, these data indicate that the microbiota plays a prominent role in controlling acute cellular rejection.…”

“…Taken together, these data indicate that the microbiota plays a prominent role in controlling acute cellular rejection. These data further suggest that antibiotic-mediated alteration of the microbiome may not uniformly decrease the degree of the cellular immune response to allografts, as previously described, 6,7 but may be context, recipient, and facility dependent.…”

“…3,14,15 We specifically focused on immune responses in the C57BL10(B10) to C57BL6(B6) model of left single lung transplantation due to well-described phenotypic changes of acute and chronic rejection that resemble human pathology. 3,7,14,15 Seven days postengraftment, none of the grafts had gross or histologic evidence of collapse, or parenchymal or obliterative airway fibrosis (O-AF) ( Figure 1A). B10 grafts placed into B6J or B6E Indiana recipients, however, demonstrated severe inflammatory changes with high levels of vascular cuffing and increased numbers of graft infiltrating T cells compared to grafts placed into B6E Maryland recipients ( Figure 1B).…”

“…It has been previously demonstrated that in C57BL/6 mice, specifically obtained from the ENVIGO Indiana facility, induction of dysbiosis with broad-spectrum antibiotics can alter antigen-presenting capacity of myeloid cells ameliorating rejection of both skin and heart grafts due to impaired priming of alloreactive T cells. While multiple aspects of the gut microbiota have been demonstrated to contribute to pulmonary as well as systemic immune responses,7,34 7 These data are supported by human observational studies that use of antibiotics can downregulate the immune response and decrease the efficacy of tumor immunotherapy.…”