Proinflammatory Mediators Leading to Graft Transition Syndrome in the Context of Living Donor Kidney Transplantation

Our group has previously shown that long-term acceptance (tolerance) of kidney graft in the absence of immunosuppressive drugs is feasible in HLA-matched recipient cohort. Such tolerance is achieved through persistent mixed chimerism in recipient (i.e., continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells) alongside kidney engraftment. However, achieving such tolerance in haplotype-matched patients with complete withdrawal of immunosuppressive drugs remains an unmet clinical need. Mismatches in HLA alleles in haplotype-matched recipient-donor pairs are speculated to induce graft transition syndrome (GTS), which poses a challenge in establishing persistent mixed chimerism. In this study, we aimed to identify immune mediators of GTS in haplotype-matched kidney recipient sera and PBMCs following donor hematopoietic CD34 + progenitors and CD3 + T cells. Recipients were infused donor progenitors and T cells on day 11 post-kidney transplant. We analyzed recipient serum samples collected pre-transplant (baseline) and on days 14 and 17 post-transplant using multiplex proteomic platform- NULISA. Haplotype-matched recipients with persistent mixed chimerism within 90 days of engraftment showed significantly lower levels of proinflammatory chemokine CXCL11, soluble lymphocyte-activation gene 3 (LAG3), and advanced glycation end products receptor (AGER) on day 14 and 17 compared to respective sample set from recipients, who lost chimerism within 90 days. Proinflammatory immune response in days following infusion of donor hematopoietic progenitors and T cells implies lower likelihood of mixed chimerism in haplotype-matched kidney recipients. Treatment strategies mitigating such in vivo inflammation may improve the possibility of immunosuppressive drug-free tolerance in this cohort.