The Johns Hopkins RTR Consortium: A Collaborative Approach to Advance Translational Science and Standardize Clinical Monitoring of Restorative Transplantation

Abstract

For many devastating combat and civilian injuries where conventional reconstruction is inadequate, vascularized composite allotransplantation (VCA) has become a viable alternative. However, the toxicities and adverse effects of high dose immunosuppressive drugs have curtailed wider application. Thus the purpose of this project is to develop novel clinically relevant immunosuppression sparing regimens allowing for immunomodulation and tolerance induction after VCA using a translational large animal model. A total of 24 MGH miniature swine underwent heterotopic osteomyocutaneous hind limb transplantation across full swine leukocyte antigen mismatch. All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction. Aim1: Group I was treated with high-dose tacrolimus (15-20ng/ml) maintenance therapy. Group II was treated with low-dose tacrolimus (4-6ng/ml). Group III received low-dose tacrolimus and 20 mg/kg of CTLA4-Ig administered on POD2, 7, 14, 30, 60, 90, and 120. Aim2: Group IV received transient high-dose tacrolimus until POD60. Group V received transient high-dose tacrolimus until POD60 and was switched to CTLA4-Ig administered on POD60, 85, 100, 120 and 150. Aim3: Group VI received the non-myeloablative conditioning plus bone marrow infusion (BMI) and intermediate dose tacrolimus (10-15 ng/ml) for 30 days only. Group VIII received the induction regimen, BMI and CTLA4-Ig and a short-term dose of tacrolimus (30 days). In all groups, graft rejection was monitored by clinical assessment and protocol skin biopsies. Alloreactivity against donor antigens was assessed using an optimized CFSE-based mixed lymphocyte reaction (MLR). All group I animals died prematurely due to infectious complications related to high dose tacrolimus treatment. 2/3 animals that received sub-therapeutic tacrolimus (group II) have rejected their grafts.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2016
Accession Number
AD1033402

Entities

People

  • Gerald Brandacher

Organizations

  • Johns Hopkins University

Tags

DTIC Thesaurus Topics

  • Allografts
  • Biological Therapy
  • Bone Marrow
  • Cells
  • Data Analysis
  • Diseases And Disorders
  • Health Services
  • Hemorrhage
  • Immunomodulation
  • Leukocytes
  • Lymphatic System
  • Lymphocytes
  • Medical Personnel
  • Surgery
  • Therapy
  • Transplants

Fields of Study

  • Biology
  • Medicine

Readers

  • Clinical Trial Research.
  • Immunology and Pathology
  • Trauma Surgery or Emergency Medicine.

Technology Areas

  • Biotechnology