Evidence for Kidney Rejection After Combined Bone Marrow and Renal Transplantation Despite Ongoing Whole-Blood Chimerism in Rhesus Macaques

Abstract

Although there is evidence linking hematopoietic chimerism-induction and solid organ transplant tolerance, the mechanistic requirements for chimerism-induced tolerance are not clearly elucidated. To address this, we used an MHC-defined primate model to determine the impact of impermanent, T cell-poor, mixed-chimerism on renal allograft survival. We compared two cohorts: one receiving a bone marrow + renal transplant (“BMT/renal”) and one receiving only a renal transplant. Both cohorts received maintenance immunosuppression with CD28/CD40-directed costimulation blockade and sirolimus. As previously demonstrated, this transplant strategy consistently induced compartmentalized donor chimerism, (significant whole-blood chimerism, lacking T cell chimerism). This chimerism was not sufficient to prolong renal allograft acceptance: the BMT/renal mean survival time (MST, 76 days) was not significantly different than the renal transplant alone MST (85 days, p= 0. 46), with histopathology documenting T-cell mediated rejection. Flow cytometric analysis revealed significant enrichment for CD28-/CD95+ CD4+ and CD8+ Tem cells in the rejected kidney, suggesting a link between CD28-negative Tem and costimulation blockade-resistant rejection. These results suggest that in some settings, transient T cell-poor chimerism is not sufficient to induce tolerance to a concurrently placed renal allograft and that the presence of this chimerism per se is not an independent biomarker to identify tolerance.

Use of CTLA4Ig for Induction of Mixed Chimerism and Renal Allograft Tolerance in Nonhuman Primates

“…However chimerism eventually disappeared after dicontinuation of immunosuppression (30). In their subsequent study, they performed combined kidney and bone marrow transplantation using the same conditioning regimen (31). In contrast to our results, all five recipients rejected their kidney allografts despite successful chimerism induction.…”

The Knife’s Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques

“…Our previous work demonstrated the successful induction of long-lived (> 1 year) myeloid-predominant chimerism with this regimen. (1, 35–38) However, unlike in mice, reduced-intensity busulfan-only conditioning in NHP did not lead to significant T cell chimerism (35, 36) and without significant T cell chimerism, the donor hematopoietic graft was eventually rejected by host T cells (35, 36, 39) (at a pace directly related to the degree of MHC disparity). (36) This transient chimerism did not induce tolerance to renal allografts.…”

Successful Tolerance to Fully MHC Disparate Renal Allografts via Donor Hematopoietic Mixed Chimerism in Non-Human Primates

“…A recent article in AJT by Ramakrishnan et al (1), referring to a recent report from our group (2), suggested that we had achieved tolerance of renal allografts in non-human primates via mixed chimerism only in highly MHC-matched transplant pairs. This interpretation of our experience is not fully accurate.…”