A Novel Graft Implanted Macrophage-Enzyme Responsive Immunosuppressive Therapy (MERIT) to Prevent Chronic Rejection in Vascularized Composite Allotransplantation
Abstract
Despite evolving clinical experience and progress in the understanding of the biology of vascularized composite allografts (VCAs), one of the main factors preventing wider acceptance or routine clinical application is the associated adverse effects of long-term immunosuppression. Anti-rejection therapy can lead to diabetes mellitus, nephrotoxicity, osteonecrosis, leukopenia, hypertension, hyperlipidemia, and opportunistic bacterial and viral infections. Since VCAs are non-life-saving procedures, the risks and toxicity of immunosuppression must be carefully balanced against their potential life-enhancing benefits in recipients. Unlike most solid organ transplantations (SOTs), VCAs offer unique opportunities for local delivery of immunosuppressive medications directly to the graft. The rationale for such site-specific, transplant- delivered immunosuppression is to reduce systemic exposure and global adverse effects. Our team has identified that specific immune cells called macrophages are major players during inflammatory responses after VCA transplantation. In prior studies, we delivered immunosuppressive drugs packaged in “gels” directly by injection to the VCA transplant and effectively controlled rejection. Specifically, this gel is unique, as it only releases the drug in the presence of inflammation and macrophages, thus reducing the levels of the drug in the blood to negligible amounts and increasing the levels in the transplanted tissues to suppress rejection. Immunosuppressive drugs can be encapsulated in such gels to create “inflammation-responsive depots” that can be customized for controlled, continuous, or on-demand local release in VCA tissues in response to biological stimuli (such as the beginning of rejection). These systems can be embedded in transplanted tissue to provide programmed release of drugs over extended periods of time and enhance the therapeutic effect. Here, we propose a novel gel called the Macrophage-Enzyme Responsive Immunosuppressive Therapy (MERIT) that combines two drugs, sirolimus and mycophenolic acid, which are not toxic to the kidney (like the conventional drug, tacrolimus, used widely in VCA) and also prevent chronic rejection. Chronic rejection is the bane of VCA, causing loss of grafts due to narrowing of blood vessels. Hypothetically, site-specific graft immunosuppression such as proposed with the novel MERIT delivery platform could facilitate minimization of the overall dosing, frequency, and duration of systemic immunosuppression and also help reduce the number of systemic drugs required for desired efficacy and improved graft survival. Graft-embedded drug delivery can have a huge impact in VCA. VCA could benefit from the forefront of nanotherapeutics and biomaterial-based drug delivery, which offers the most immediate payoff for target (disabled) Service members with lower risk and morbidity. VCA could allow shorter rehabilitation and earlier return of combat Soldiers to prior professional responsibilities. We are confident that the proposed work will establish the utility of this platform as a graft-embedded drug delivery technology for chronic rejection (as well as acute rejection) mitigation, achieving a major impact specifically in VCA transplantation and more generally across many clinical applications in transplantation medicine. Gels as proposed are also promising in wide-ranging applications outside of VCA and transplantation, such as in dermatology, cardiology and cancer. It would save the Department of Defense millions of dollars in rehabilitation and retraining and, most importantly improve the quality of life, morale, and performance of Soldiers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910828
Entities
People
- Jelena M. Janjic
Organizations
- Duquesne University
- United States Army