Development of Immunologic therapies against uveitis

National Eye Institute

Investigators

Linked publications & trials

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is inaccessible to many patients with hematologic malignancies for lack of HLA-matched donors. Although nearly all patients have HLA haploidentical donors, HLA-haploidentical HCT still results in high mortality due to prohibitive rates of severe Graft-Versus-Host Disease (GVHD). Increase of proinflammatory cytokines and reduced levels of regulatory B cells (Bregs) drive GVHD development. We identified a novel IL-35-producing B cell (i35-Breg) population that inhibits inflammation and found that administering ex-vivo generated i35-Breg cells at time of transplantation suppressed GVHD in mice. We have been able to suppress GVHD for more than 3 months in more than 90% of mice with GVHD that receive i35-Breg therapy. We have shown that Camelid-driven STAT-specific Nanobody inhibits neuroinflammation and ameliorates experimental autoimmune encephalomyelitis (EAE). We show that this nanobody ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from the nanobody-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from direct suppression of encephalitogenic T-cells. The small size of this Camelid-driven pan-STAT nanobody is a promising immunotherapy for CNS autoimmune diseases including uveitis and multiple sclerosis.