IL-7 receptor blockade following T cell depletion promotes long-term allograft survival
Hoa-Le Mai, … , Sophie Brouard, Jean-Paul Soulillou
Hoa-Le Mai, … , Sophie Brouard, Jean-Paul Soulillou
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1723-1733. https://doi.org/10.1172/JCI66287.
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Research Article Immunology

IL-7 receptor blockade following T cell depletion promotes long-term allograft survival

Abstract

T cell depletion is commonly used in organ transplantation for immunosuppression; however, a restoration of T cell homeostasis following depletion leads to increased memory T cells, which may promote transplant rejection. The cytokine IL-7 is important for controlling lymphopoiesis under both normal and lymphopenic conditions. Here, we investigated whether blocking IL-7 signaling with a mAb that targets IL-7 receptor α (IL-7Rα) alone or following T cell depletion confers an advantage for allograft survival in murine transplant models. We found that IL-7R blockade alone induced indefinite pancreatic islet allograft survival if anti–IL-7R treatment was started 3 weeks before graft. IL-7R blockade following anti-CD4– and anti-CD8–mediated T cell depletion markedly prolonged skin allograft survival. Furthermore, IL-7 inhibition in combination with T cell depletion synergized with either CTLA-4Ig administration or suboptimal doses of tacrolimus to induce long-term skin graft acceptance in this stringent transplant model. Together, these therapies inhibited T cell reconstitution, decreased memory T cell numbers, increased the relative frequency of Tregs, and abrogated both cellular and humoral alloimmune responses. Our data suggest that IL-7R blockade following T cell depletion has potential as a robust, immunosuppressive therapy in transplantation.

Authors

Hoa-Le Mai, Françoise Boeffard, Julie Longis, Richard Danger, Bernard Martinet, Fabienne Haspot, Bernard Vanhove, Sophie Brouard, Jean-Paul Soulillou

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Figure 8

IL-7R blockade synergizes with treatment protocols combining T cell depletion with either CTLA-4Ig or suboptimal doses of tacrolimus.

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IL-7R blockade synergizes with treatment protocols combining T cell depl...
BALB/c mice received C57BL/6 skin graft and were treated as indicated (n = 5–6 for each group). (A) CTLA-4Ig alone only slightly prolonged graft MST compared with no treatment (11 vs. 9.5 days; P < 0.01). CTLA-4Ig combined with T cell depletion prolonged MST to 28.5 days, and the addition of IL-7R blockade to this treatment protocol further increased MST to 52.5 days (P < 0.05). (B) Low-dose tacrolimus (Tac) given from D0 only slightly prolonged graft MST compared with no treatment (11 vs. 9.5 days; P < 0.01). T cell depletion combined with low-dose tacrolimus given from either D0 or PTD12 prolonged MST to 32.5 or 33 days, respectively, and the addition of anti–IL-7Rα mAb for a duration of either 70 days or 35 days to these 2 treatment protocols further prolonged MST to beyond 90 days in the majority of mice (see figure for direct comparisons between treatment protocols with and without anti–IL-7Rα mAb). (C) Lymphocyte phenotyping on PTD90 showed that the shortening of the duration of anti–IL-7R treatment from 70 days to 35 days in the DEP + Tac D12 + a–IL-7R protocol was associated with a better lymphocyte recovery in the thymus and in the LNs. *P < 0.05.