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A Method for Murine Islet Isolation and Subcapsular Kidney Transplantation
Published on: April 13, 2011
Preclinical evaluation of tolerance induction protocols and islet transplantation in non-human primates
S P Montgomery1, D A Hale, B Hirshberg
1NIH/Navy Transplant and Autoimmunity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland 20892, USA.
Abstract:
Non-human primate studies of tolerance induction strategies in solid organ transplantation represent a critical bridge between studies in rodents and humans. Our work demonstrates that strategies involving the blockade of co-stimulatory molecules, especially the CD40-CD154 pathway, have great potential for clinical adaptation. While the combination of anti-CD154 antibody with blockade of the CD28 pathway reduced donor antibody production, graft survival was not significantly improved over that achieved with anti-CD154 antibody alone. Moreover, although long courses of steroids seem to interfere with this approach, it may be possible to combine blockade of the CD40-CD154 pathway with other conventional immunosuppressants without sacrificing efficacy. This is a key issue for reducing the risk associated with eventual clinical trials. Work in the non-human primate islet transplant model demonstrates that viable islets can be recovered, isolated and infused in a reliable fashion. It also confirms the efficacy of a steroid sparing approach to immunosuppression for islet transplantation. These data have been expanded to the kidney allograft model, setting the stage for kidney islet transplantation studies. Overall, tolerance induction and islet transplant studies in non-human primates permit the preclinical screening of promising immunomodulatory approaches developed in rodents and reduce the inherent uncertainties associated with adapting new regimens to the clinic.
Insights
Non-human primate studies show co-stimulatory molecule blockade, particularly CD40-CD154, holds promise for organ transplant tolerance. This approach may allow for reduced steroid use in islet transplantation, paving the way for clinical trials.
Area of Science:
- Transplantation immunology
- Immunomodulation
- Preclinical research
Background:
- Non-human primate models are crucial for bridging rodent and human studies in transplantation.
- Tolerance induction strategies aim to prevent immune rejection of transplanted organs.
- Co-stimulatory molecule blockade is a key area of research in transplantation.
Purpose of the Study:
- To evaluate tolerance induction strategies in non-human primates for solid organ transplantation.
- To assess the efficacy of CD40-CD154 pathway blockade in combination with other immunosuppressants.
- To investigate steroid-sparing immunosuppression for islet transplantation.
Main Methods:
- Utilized non-human primate models for solid organ and islet transplantation.
- Investigated blockade of co-stimulatory molecules, including CD40-CD154 and CD28 pathways.
- Assessed graft survival and donor antibody production.
- Evaluated steroid-sparing immunosuppression regimens.
Main Results:
- Blockade of the CD40-CD154 pathway shows significant potential for clinical adaptation in transplantation.
- Combining anti-CD154 with CD28 blockade reduced donor antibody production but did not improve graft survival.
- Steroid-sparing immunosuppression is effective for islet transplantation in non-human primates.
- The CD40-CD154 blockade can potentially be combined with other immunosuppressants.
Conclusions:
- Non-human primate studies are essential for preclinical screening of immunomodulatory approaches.
- CD40-CD154 pathway blockade is a promising strategy for tolerance induction in organ transplantation.
- Steroid-sparing protocols are viable for islet transplantation, reducing risks for clinical application.
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