Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study

Abstract

Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule-focused therapies.

Keywords: animal models: nonhuman primate; antigen presentation/recognition; basic (laboratory) research/science; costimulation; immunobiology; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppression/immune modulation; kidney transplantation/nephrology; lymphocyte biology: differentiation/maturation; translational research/science.

Figure 1.

Rejection-free survival. Median survival time for untreated (historic) control was 7 days, for belatacept-alone group 81 days, and undefined for the belatacept + Splenectomy treatment group. Improvement in survival is significant by log-rank test (P = 0.027).

Figure 2.

Longitudinal absolute lymphocyte count. For both groups, absolute lymphocyte count remains stable longitudinally. No significant differences were observed in baseline nor in longitudinal absolute lymphocyte count during belatacept maintenance immunosuppression. Following complete immunosuppression withdrawal, the surviving animal in the belatacept control group exhibited modestly increased lymphocyte counts in comparison to animals that had received splenectomy at the time of transplantation.

Figure 3a+b.

(A) longitudinal relative distribution of CD4+ T_naïve, T_central memory, and T_effector cells for animals that received splenectomy at the time of transplantation. Relative to the longitudinal distribution of control belatacept animals in (B), animals that underwent splenectomy exhibited a more prompt and prominent tendency towards a CD4+ T_naïve predominance.

Figure 4a+b.

(A) longitudinal relative distribution of CD8+ T_naïve, Tcentral memory, and Teffector cells for animals that received splenectomy at the time of transplantation. Relative to the longitudinal distribution of control belatacept animals in (B), animals that underwent splenectomy exhibited a less prominent tendency towards CD8+ Tem predominance early, though no significant difference between groups was identified in any memory compartment across later time points.

Figure 5.

Longitudinal relative distribution of B cells for animals that received splenectomy in addition to belatacept maintenance immunosuppression. In the first months post-transplant, animals that received a splenectomy at the time of transplantation subsequently developed a naïve B-cell predominance.