Role of IL-12 family cytokines in autoimmune Uveitis

National Eye Institute

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Abstract

AAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment for aggressive hematologic malignancies. However, risk of developing graft-versus-host disease (GVHD) is a significant barrier to allo-HSCT. GVHD is a debilitating condition with high mortality rates and current therapeutic options for GVHD are limited, with corticosteroids being the standard treatment. However, adverse effects of steroids make prolonged use difficult, necessitating the development of safer therapies. IL-35-producing B-cells (i35-Bregs) have emerged as critical regulators of immunity during autoimmune diseases. We investigated whether i35-Bregs immunotherapy can suppress and mitigate GVHD. A single dose of 1.5x106 i35-Breg cells reduced severity of GVHD and prolonged GVHD survival, with more than 70% i35-Breg-treated mice surviving beyond day-90 post-transplantation while observing 100% mortality among untreated mice by day-45. i35-Bregs also secrete exosomes that produce IL-35 (i35-exosomes). i35-exosomes suppress GVHD by increasing bystander lymphocytes coated with suppressive i35-exosomes. We found that i35-Bregs and i35-exosomes play critical roles in mitigating GVHD. The combination of i35-Breg and i35-exosome immunotherapy maybe an effective strategy for treating GVHD and other inflammatory diseases.