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

Abstract

Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4 + Foxp3 + regulatory T cells (T regs ) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad-spectrum antibiotics decreases T regs and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3-driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of T regs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through T reg -dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period. K E Y W O R D Sanimal models: murine, basic (laboratory) research/science, bronchiolitis obliterans (BOS), immunosuppression/immune modulation, lung disease: immune/inflammatory, lung transplantation/pulmonology, rejection: acute, rejection: chronic

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

“…21,22,25,[34][35][36][37][38] We have found that fibrosis diminishes over time with surgical experience, and currently we observe minimal fibrosis in allografts not subjected to IRI, in contrast to our earlier data. Allograft fibrosis in the B10→B6 LT model is highly variable among different surgeons and research groups, whereas AR is mild but reproducible.…”

“…Allograft fibrosis in the B10→B6 LT model is highly variable among different surgeons and research groups, whereas AR is mild but reproducible. 21,22,25,[34][35][36][37][38] We have found that fibrosis diminishes over time with surgical experience, and currently we observe minimal fibrosis in allografts not subjected to IRI, in contrast to our earlier data. 20 We therefore hypothesized that the limited fibrotic WIT nor 30 minutes CIT plus 60 minutes WIT caused CR (not shown).…”

“…22,34 We have found that fibrosis diminishes with time and operator experience -as illustrated by a comparison between our current AlloMin grafts (Figure 3A,D) and equivalent grafts in our recent reports. 20,25 Although the precise reasons for reduced fibrosis are unclear, it is likely that inflammation resulting from preservation and surgical injury, and other factors such as the microbiome, 38,47 influence its development.…”

The emerging role of regulatory T cells following lung transplantation

“…[20][21][22] Direct T cell contact with antigen-presenting cells also appears to be required for peripheral conversion of naive T cells into Tregs, as this process requires engagement of T cell receptors and costimulatory molecules. 26 23,24 For example, we have shown that selective elimination of MHCII expression on non-hematopoietic cells in the lung resulted in reduced local generation of Tregs, which was associated with enhanced inflammation.…”

“…To this end, we have recently demonstrated that recipient microbiota has a significant impact on the pulmonary and systemic levels of Tregs following lung transplantation, suggesting a potential link between dysbiosis and an increased risk of acute and chronic rejection. 26…”