A Pilot Trial Targeting the ICOS–ICOS-L Pathway in Nonhuman Primate Kidney Transplantation

Abstract

Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4+ and CD8+ T cells expressed ICOS, and ICOS+ T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS+ T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8+CD28−, but importantly, very few CD8+CD28− T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in nonhuman primates. This may relate to selective loss of ICOS with CD28 loss.

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model

“…MHC typing for both class I and class II was performed by 454 pyrosequencing (University of Wisconsin, Madison, WI, USA). Transplantation was performed in a domino fashion to maximize the utility of the available animals, with each animal serving as a kidney donor prior to receiving a transplant as described previously (16, 22, 35). Left donor nephrectomy was performed at least 3 weeks prior to transplantation.…”

“…These samples were embedded in paraffin with subsequent sectioning and hematoxylin and eosin staining. Staining for high affinity LFA-1 was performed on specimens from our previous NHP transplant studies (35). Samples were identified, then stained after deparaffinization using AL-579 as a primary antibody and visualized using the LSAB+ labeled Streptavidin-Biotin kit (Dako; Carpenteria, CA, USA).…”

T Cell Cosignaling Molecules in Transplantation

“…Despite the association of reduced ICOS expression with increased graft survival in the presence of selective CD28 blockade, this reduction in ICOS expression was found to not be mechanistically responsible for the diminished rejection response, in that overexpression of ICOS on the surface of donor-reactive T cells failed to enhance alloreactive CD8 + T cell responses or precipitate rejection (Liu et al, 2015a). The conclusion that ICOS-mediated signals may play a subdominant role in the initiation and differentiation of alloreactive T cell responses is further solidified by recent evidence that ICOS blockade, either alone or in combination with belatacept, resulted in no measurable effect on allograft rejection in a non-human primate model of kidney transplantation (Lo et al, 2015). However, these findings do not preclude a role for ICOS in the provision of help for the production of alloantibody.…”

Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

“…Whereas peritransplant CTLA-4Ig treatment extended the survival of allografts subjected to minimal (e.g., 30 minutes) CIS by more than 7 weeks, this treatment extended the survival of allografts subjected to prolonged (e.g., 6-8 hours) CIS by only a few days; this rejection was mediated by the endogenous memory CD8 + T cells. These results were reminiscent of the costimulatory blockade-resistant endogenous memory CD8 + T cell responses that mediate acute rejection and decrease graft survival in nonhuman primate (NHP) and human allograft recipients (28)(29)(30)(31). How such endogenous memory CD8 + T cells are activated within allografts to mediate this early severe graft injury and failure has not been determined.…”