Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection.

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Epitope-based ligation of ICAM-1: Therapeutic target for protection against the development of rheumatoid arthritis.

Identification of a particular epitope on the domain 2 of human ICAM-1 led us to focus on its role in the treatment of rheumatoid arthritis (RA). Key observations from our previous xenotransplantation research included the generation of tolerogenic DCs, antigen-specific T-cell tolerance, and reduced production of inflammatory cytokines. The critically important point is the fact that it works initially on DC maturation. Ligation of this epitope with a recognizing antibody, MD-3, was also able to create a tolerogenic environment in RA in a manner sililar to that created by xenotransplantation. In this study, we noted that the disease progression, in terms of arthritis score and histopathology of joints, was significantly less severe in the MD-3-treated group than in the vehicle-treated group. Defective production of IL-6 and reduced proliferation of collagen-specific T cells were most remarkable laboratory findings. This type of ligation has a greater advantage over other types of therapeutics, in a sense that simple injection of this antibody inhibits antigen-specific T cell response. Due to the possibility of viral infection in this process, we regularly monitored cytomegalovirus reactivation status without detection of any viral gene replication. We are hoping that remarkable specializations that this interaction has, would be a promising target for therapeutic antibody in RA.

Attenuation of Experimental Autoimmune Encephalomyelitis in a Common Marmoset Model by Dendritic Cell-Modulating Anti-ICAM-1 Antibody, MD-3.

MD-3 is a novel anti-human ICAM-1 monoclonal antibody that induces T cell tolerance in humanized mice via modulation of dendritic cell differentiation and efficiently suppresses the development of collagen-induced arthritis. This effect has also been observed in xenograft rejection in nonhuman primates, where grafts survived for more than 2.5 years following MD-3 administration. Here, we show that MD-3 can attenuate experimental autoimmune encephalomyelitis (EAE) that was induced in common marmoset monkeys by immunization with human myelin oligodendrocyte glycoproteins. MD-3 administration was initiated 1 week after immunization and efficiently delayed the development of EAE phenotypes, although the disease was not completely prevented. Based on the results of histopathological examination, MD-3 treatment greatly suppressed total inflammation with respect to demyelination, as well as T cell and microglial infiltration in the brain. However, the antibody response against myelin oligodendrocyte glycoprotein was not suppressed with this treatment protocol. These observations suggest that the MD-3 antibody has beneficial effects on the treatment of EAE via the suppression of T cell-mediated cellular responses.