Th17 cell inhibition in a costimulation blockade‐based regimen for vascularized composite allotransplantation using a nonhuman primate model

Abstract

Vascularized composite allotransplantation (VCA) is challenged by the morbidity of immunosuppression required to prevent rejection. The use of highly specific biologics has not been well explored in VCA. Given that psoriasis is T-cell mediated, as is rejection of skin-containing VCAs, we sought to assess the role of ustekinumab and secukinumab, which are approved to treat psoriasis by inhibiting Th17 cells. We combined these agents with belatacept and steroids in a VCA nonhuman primate model. Group I consisted of belatacept and steroids, group II was belatacept, ustekinumab with steroid taper, and group III was belatacept, secukinumab with steroid taper. Three animals were transplanted in each group. In group I, the mean graft survival time until the first sign of rejection was 10 days whereas in group II and III it was 10.33 and 11 days, respectively. The immunohistochemistry analysis showed that the number of IL-17a + cells and the intensity of IL-17a expression were significantly reduced in both dermis and hypodermis parts in groups II and III when compared to group I (P < 0.01). Ustekinumab and secukinumab led to less T-cell infiltration and IL-17a expression in the allograft but provided no benefit to belatacept and steroids in VCA survival.

Costimulation Blockade in Vascularized Composite Allotransplantation

“…Currently, belatacept seems as a promising agent that prolongs the rejection free survival when added to tacrolimus in experimental VCA models ( 38 ). However, belatacept in combination with steroids alone failed to prevent acute rejection and resulted in an average rejection free survival (time from transplant to early signs of rejection) of 10 days compared to an average rejection free survival 31.1 days in animals treated with tacrolimus, MMF and steroids ( 93 , 105 ). As it has been shown by us and others, the use of belatacept resulted in inhibition of DSA formation ( 39 , 93 ).…”

“…However, belatacept in combination with steroids alone failed to prevent acute rejection and resulted in an average rejection free survival (time from transplant to early signs of rejection) of 10 days compared to an average rejection free survival 31.1 days in animals treated with tacrolimus, MMF and steroids ( 93 , 105 ). As it has been shown by us and others, the use of belatacept resulted in inhibition of DSA formation ( 39 , 93 ). As anticipated and similar to other organ transplants graft vasculopathy and antibody mediated rejection in VCA are associated with the presence of DSA or C4d deposits ( 106 – 110 ).…”

“…The comparison with a historic cohort, treated with the standard immunosuppression (Tacrolimus, MMF, Methylprednisolone), revealed significantly shorter interval to acute rejection in all groups (≤14 days), independent of the Th17 inhibition, compared to controls (mean survival = 31.1 days). However, historic controls without costimulation blockade showed a significant increase in DSA production at rejection, while all belatacept treated animals did not develop post-transplant DSA at rejection ( 93 ).…”

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

“…Wachtman et al (40) first evaluated the efficacy of combination CTLA4-Ig + tacrolimus compared to tacrolimus alone in a Yucatan miniature swine model and found that the addition of CTLA4-Ig significantly increased survival of grafts from a mean of 31 days to > 150 days. Atia et al (41) hypothesized that the addition of Th17 blockade to a CoB based regimen would limit T cell infiltration and may prolong graft survival. Treatment with ustekinumab (anti-IL12/23) and secukinumab (anti-IL17A) was shown to decrease skin T cell infiltration and expression of IL17A but was not associated with prolonged graft survival.…”

Vascularized composite allotransplants as a mechanistic model for allograft rejection – an experimental study

“…These include direct recognition of widely distributed donor MHC molecules on passenger leukocytes. These, combined with ubiquitous reperfusion events, plausibly allow for peripheral antigen presentation by activated non‐professional antigen‐presenting cells (APCs) such as vascular endothelium [7,8]. Additionally, heterologous immunity provides mechanisms by which cells primed via prior conventional protective immune mechanisms can undergo anamnestic activation to novel alloantigens without the need for a de novo priming event.…”