Inducible Costimulator (ICOS) Is up-Regulated in Dogs with Graft Versus Host Disease and Graft Rejection Following Non-Identical Hematopoietic Cell Transplantation

Abstract 4109

Inducible co-stimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4⁺ and CD8⁺ T-cells following their activation. Evidence suggests ICOS functions as an essential immune regulator and ICOS blockade is a potential target for allogeneic transplantation. We have used the canine model to develop several strategies for hematopoietic stem cell transplantation that have been successfully translated into the clinic. Here we describe the production and testing of monoclonal antibodies (mAb) directed against canine ICOS and determined the expression profile of ICOS in dogs. Canine ICOS was expressed in an inducible pattern on up to 89% of T-cells activated by Con A, anti-CD3 plus anti-CD28 mAb and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells obtained from dog leukocyte antigen nonidentical dogs. Significant augmentation of the immunosuppressive effects of ICOS blockade was observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig (CTLA4-Ig) or cyclosporine. ICOS expression was significantly up-regulated on T-cells collected from the peripheral blood, lymph nodes and spleen from dogs undergoing graft rejection or chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Dogs that remained mixed chimeric expressed ICOS at levels comparable to normal dogs. Analysis of the peripheral blood CD3+ T-cells isolated from dogs showed a significant up-regulation of ICOS expression 3 days but not 6–7 days before the diagnosis of chronic GVHD. Pharmacokinetic studies of ¹²³I-labled anti-canine ICOS showed normal blood clearance profiles. These studies demonstrated that an antagonistic anti-canine ICOS mAb may have application in the prevention or treatment of GVHD in an outbred animal model shown to reliably translate novel hematopoietic cell transplantation therapies to the clinic.