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Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation.

ABSTRACT: Research in transplant immunology using non-human primate (NHP) species to evaluate immunologic strategies to prevent rejection and prolong allograft survival has yielded results that have translated successfully into human organ transplant patient management. Other therapies have not proceeded to human translation due to failure in NHP testing, arguably sparing humans the futility and risk of such testing. The NHP transplant models are ethically necessary for drug development in this field and provide the closest analogue to human transplant patients available. The refinement of this resource with respect to colony MHC typing, reagent and assay development, and availability to the research community has greatly enhanced knowledge about transplant immunology and drug development.

SUBMITTER: Fitch Z

PROVIDER: S-EPMC6599548 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation.

Fitch Zachary Z Schmitz Robin R Kwun Jean J Hering Bernhard B Madsen Joren J Knechtle Stuart J SJ

Transplantation reviews (Orlando, Fla.) 20190405 3

Research in transplant immunology using non-human primate (NHP) species to evaluate immunologic strategies to prevent rejection and prolong allograft survival has yielded results that have translated successfully into human organ transplant patient management. Other therapies have not proceeded to human translation due to failure in NHP testing, arguably sparing humans the futility and risk of such testing. The NHP transplant models are ethically necessary for drug development in this field and ...[more]

PMID: 31027947

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Project description:Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5-12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-? (TNF?), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNF?, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.

Dataset Information

Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation.

Publications

Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation.

Similar Datasets

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