Currently, hematopoietic stem cell transplantation is the main approach to fight against some cancers, such as leukemia. The most important side effect of this treatment is the development of graft versus host disease. Despite the development of different therapies, GVHD occurs in 40 to 60% of the patients treated with HSCT. GVHD is characterized by the over production of inflammatory cytokines and the reduction of regulatory T cells number. Indeed, a treatment modifying the balance between effector and regulatory cells seems to be a promising approach against GVHD. The CD45RC molecule can be used to define two different subpopulations in rat and human. Effector T cells express high level of CD45RC (CD45RC^high) while regulatory T cells express low level of CD45RC (CD45RC^low). We have already demonstrated that targeting the CD45RC isoform with a short term anti-CD45RC mAb treatment decrease transiently effector cells and improve regulatory function of Tregs cells in a heart allograft rat model (Picarda E, Bézie S, Boucault L, JCI insight, 2017).
We set up two different models of GVHD. We injected T cells from Lewis rat donor to irradiated Lewis/BN F1 rats to induce GVHD (semi-allogenic model). We also use a model of irradiatedimmunodeficient NSG mice which received PBMC from human healthy volunteers (xenogeneic model). In these two models, animals were treated with short term anti-CD45RC mAb antibodies.
In the rat semi-allogeneic model, the treatment with an anti-rat CD45RC mAb antibody (1.5 mg/kg every 2.5 days during 30 days) associated with a sub optimal dose of rapamycin (0.4 or 0.8 mg/kg each day during 10 days) significantly delayed GVHD development for all animals and 55% of the treated rats survived at long-term (>100d). We observed an important decrease of CD45RC^high cells during the treatment, demonstrating the efficacy of the treatment. Moreover, the depletion of CD45RC^high T cells by cell sorting before the injection to Lewis/BN F1 rats prevented the development of GVHD for 75% of the recipients. We analyzed different organs to compare GVHD damages between rats treated with either anti-CD45RC mAb or isotype control. We also studied the effect of the treatment on the function of regulatory T cells in vitro.
In the NSG mice xenogeneic model, we tested an anti-human CD45RC mAb administered alone every 2.5 days during 30 days. We observed that this treatment efficiently delayed the weight loss of the mice following human PBMCs infusion in NSG mice and prolonged their survival. Furthermore, we tested the injection of PBMC depleted of CD45RC^high cells by cell sorting and demonstrated that the depletion of the PBMCs before the injection induced long term survival in 87% of the mice.
Our results highlighted the potential of a short term anti-CD45RC mAb as a new innovative therapy against graft versus host disease.