Establishment of New Methods for Chronic Antibody Mediated Renal Rejection Model with Clinical Immunosuppressive Drugs in Non-Human Primates
Pharmacology Research Labs., Astellas Pharma Inc, Tsukuba, Ibaraki, Japan
Meeting: 2013 American Transplant Congress
Abstract number: C1207
Background
Despite the improvement of immunosuppressive drugs and therapeutic regimens, long-term renal graft survival is still an unsolved problem. The purpose of this study is to establish the monkey model which can develop chronic antibody mediated rejection within short term post-Tx under sub-therapeutic dose of immunosuppressive drugs.
Methods
Four male cynomolgus monkeys were used in study I and II respectively. Donor and recipient pairs were selected for compatible ABO blood types, negative in anti-donor antibodies and mismatched MLR. The observation period was 6 months after kidney transplantation (KTx). In study I, the recipients were administrated the therapeutic dose of tacrolimus (2 mg/kg, p.o) for three weeks and subsequently the dose was reduced to 1 mg/kg until the end of the observation period. In addition, mycophenolate mofetil (15 mg/kg, s.c) was also administered for overall period. In the case of plasma creatinine levels were increased greater than 3 mg/dl, the recipients were treated with anti-rejection therapy. In study II, the treatments were similar to study I except for the recipients were administrated the sub-therapeutic dose of tacrolimus (1 mg/kg, p.o) from the beginning of the study.
Results
Study I. Two of four recipients showed an increase in plasma creatinine levels from 4 or 8 weeks after KTx respectively, and were treated with anti-rejection therapy. These two recipients indicated positive in anti-donor antibodies, proteinuria and pathological changes in allograft including C4d deposition and interstitial fibrosis. The other two recipients showed no obvious changes in plasma creatinine levels or pathological diagnosis.
Study II. In order to improve the manifestation frequency, the dose of tacrolimus was reduced to 1 mg/kg as sub-therapeutic dose. As a result, the chronic antibody mediated rejections (CAMR) of renal allografts were identified in all four recipients.
Conclusions
This study was designed to induce CAMR within 6 months by using immunosuppressants which are widely used in clinical setting. We established monkey model for renal allograft chronic rejection in which acute rejection and AMR can be observed due to insufficient immunosuppressant medication.
To cite this abstract in AMA style:
Maeda M, Tsujimoto S, Fukahori H, Oshima S, Nakamura K, Marui T, Higashi Y, Seki N, Uchida W. Establishment of New Methods for Chronic Antibody Mediated Renal Rejection Model with Clinical Immunosuppressive Drugs in Non-Human Primates [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/establishment-of-new-methods-for-chronic-antibody-mediated-renal-rejection-model-with-clinical-immunosuppressive-drugs-in-non-human-primates/. Accessed May 14, 2025.« Back to 2013 American Transplant Congress