Immunosuppression monotherapy does not protect donor leukocytes from depletion post MHC-mismatched kidney transplantation in mice
Sarah Dart1, Sean O'Halloran3, Liu Liu1, Wen Hua Huang1, Jaskirat Kaur1, Xiao Zhang1, Amy Prosser2, Monalyssa Watson1, Andrew Lucas2, Gary Jeffrey1,5, David Joyce2,3, Michaela Lucas1,4.
1Medical School, The University of Western Australia, Perth, Australia; 2School of Biomedical Science, The University of Western Australia, Perth, Australia; 3Department of Clinical Pharmacology and Toxicology, Sir Charles Gairdner Hospital, PathWest Laboratory Medicine, Perth, Australia; 4Department of Immunology, Sir Charles Gairdner Hospital, PathWest Laboratory Medicine, Perth, Australia; 5Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
Background: The retention of donor tissue-resident leukocytes within a transplanted organ is likely to be important to graft health and survival post-transplantation. We have previously shown that in the absence of immunosuppression, donor tissue-resident leukocytes are depleted following MHC-mismatched transplants, due to infiltrating recipient effector leukocytes. We hypothesised, therefore, that the retention of donor leukocytes described following mismatched transplants in humans is a result of immunosuppressive therapy, which targets recipient effector cells. In this study, we investigated the impact of different immunosuppressive agents as monotherapies on the retention of donor leukocytes after MHC-mismatched transplantation.
Methods: We developed immunosuppression regimens using clinically-relevant levels of immunosuppressive medications including tacrolimus and mycophenolate, and treated mice receiving MHC-mismatched kidney transplants. At seven days post-transplant, we compared the donor leukocyte retention and recipient leukocyte responses of mice on immunosuppression to those without.
Results: As expected after immunosuppression treatment, the circulating lymphocyte count was decreased. Simultaneously, the absolute number and proliferation of recipient lymphocytes within the graft and peripheral organs were reduced in comparison to immunocompetent controls. Immunosuppression also altered macrophage polarisation within the graft, to a less pro-inflammatory phenotype. Interestingly, our preliminary data showed that despite the decrease in recipient leukocyte infiltration, and a less inflammatory microenvironment within the graft, treatment with a single immunosuppressive agent did not improve donor leukocyte retention post-transplantation.
Conclusions: This highlights the requirement for the use of multiple immunosuppressive agents to sufficiently suppress recipient effector leukocyte responses, not only for graft tolerance but for donor leukocyte retention.
Hackett Postgraduate Research Scholarship. Australian Government Research Training Program Scholarship. Sir Charles Gairdner and Osborne Park Health Care Group RAC Grant (MRGP21-22_24).
right-click to download