Organ Preconditioning with Mitochondrial Elongating Agents M1/Mdivi1 in Transplantation
M1/Mdivi1 as a novel treatment to reduce immunogenicity in organ transplantation Technology: Addition of M1 and Mdivi1 drugs in organ preservation solutions can reduce the immunogenicity of the donor organ’s microvascular endothelial cells (ECs), thereby promoting allograft immune tolerance. Inventors at MUSC have found that the use of M1 (a mitochondrial fusion promoter) and Mdivi1 (a mitochondrial fission inhibitor) as a combination to pretreat microvascular ECs can influence the immune response mediated by allogeneic T-cells. M1/Mdivi1 pretreatment promoted mitochondrial elongation and reduced ICAM-1 and VCAM-1 adhesion molecule expression in ECs (data not shown). Moreover, in a co-culture model, M1/Mdivi1 pretreatment reduced the amount of cytotoxic proteins (granzyme B and IFNγ) released by allogeneic CD8+ T-cells via increasing PD-L1 expression on EC surface (Figure 1). Overall, this research suggests that applying M1/Mdivi1 treatment during organ storage can be a novel approach to induce graft tolerance in organ transplantation by reducing EC immunogenicity toward alloreactive T-cells. Overview: Transplantation is a widely accepted and highly successful therapy for end-stage organ disease. Although, success rates and survival have increased, largely in part due to immunosuppression regimes such as Tacrolimus, cyclosporine and sirolimus etc., immunological events that occur early in the life of the graft significantly affects long-term survival. Current solutions do not modulate immunologic injury during donation, nor do they prepare the donor organ for oncoming immunological attack by the host immune system. Donor organ ECs upon organ procurement and preservation are injured, activated, and act as antigen-presenting cells to stimulate alloreactive memory T-cells that mediate graft damage. Recent studies have shown that modulating mitochondrial dynamics (fusion-fission) can alter the functions of both T-cells and antigen-presenting cells. Importantly, forcing mitochondrial fusion and inhibiting fission can maintain the integrity of the microvasculature after injury by stabilizing the mitochondrial structure. Applications: M1/Mdivi1 treatment as an additive to cryopreservation solutions to reduce immunogenicity of ECs.Advantages: M1/Mdivi1 treatment as a novel therapeutic approach to induce graft tolerance in organ transplantation.Keywords: M1/Mdivi1, microvasculature endothelial cells, mitochondria, fusion-fission, graft immune tolerance.Related Publications: Inventors: Satish N. Nadig, Carl Atkinson, Danh T. TranPatent Status: Provisional Patent Filed-12/29/2017MUSC FRD Technology ID: P1790
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