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      Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival

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          Abstract

          <p class="first" id="d2150365e400">The targeted delivery of therapeutic drugs to lymph nodes (LNs) provides an unprecedented opportunity to improve the outcomes of transplantation and immune-mediated diseases. The high endothelial venule is a specialized segment of LN vasculature that uniquely expresses peripheral node addressin (PNAd) molecules. PNAd is recognized by MECA79 mAb. We previously generated a MECA79 mAb–coated microparticle (MP) that carries tacrolimus. Although this MP trafficked to LNs, it demonstrated limited therapeutic efficacy in our transplant model. Here, we have synthesized a nanoparticle (NP) as a carrier of anti-CD3, and optimized the conjugation strategy to coat the NP surface with MECA79 mAb (MECA79-anti-CD3-NP) to enhance LN accumulation. As compared with nonconjugated NPs, a significantly higher quantity of MECA79-NPs accumulated in the draining lymph node (DLN). Many MECA79-NPs underwent internalization by T cells and dendritic cells within the LNs. Short-term treatment of murine cardiac allograft recipients with MECA79-anti-CD3-NP resulted in significantly prolonged allograft survival in comparison with the control groups. Prolonged graft survival following treatment with MECA79-anti-CD3-NP was characterized by a significant increase in intragraft and DLN Treg populations. Treg depletion abrogated the prolongation of heart allograft survival. We believe this targeted approach of drug delivery could redefine the methods of administering immune therapeutics in transplantation. </p>

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          Most cited references53

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          Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

          In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R--no rejection (no change from 1990); Grade 1 R--mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R--moderate rejection (1990 Grade 3A); and Grade 3 R--severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the "A" and "B" designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.
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            Immunosuppressive drugs for kidney transplantation.

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              T-cell function and migration. Two sides of the same coin.

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                Author and article information

                Journal
                Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                August 23 2018
                October 2 2018
                October 2 2018
                October 2 2018
                Article
                10.1172/JCI120923
                6205374
                30277476
                b2f660b2-09f0-4155-8491-0ab54c70c971
                © 2018
                History

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