Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Myeloid derived suppressor cells (MDSCs) have been demonstrated to be critical for the induction of tumor induced T cell tolerance and have also been shown to have a role in allograft tolerance. This is thought to be through paracrine effects as well as through the expansion of T regs and B regs. While the majority of cell therapy focus has been on the ex vivo expansion of T regs, we wanted to determine if we could expand these potent suppressor cells in vivo and delay or prevent allograft rejection.
*Methods: To induce MDSCs, C57Bl/6J mice were injected with alum i.p. every other day for 5 days for a total of 3 doses. Spleens were then examined at different time points for the presence of either monocytic MDSCs (M-MDSCs -Ly6C+Cd11b+) or granulocytic MDSCs (G-MDSCs- Ly6G+CD11b+) via flow cytometry. To measure in vitro MDSC induced T cell suppression, spleens from either saline or alum C57Bl/6J mice were harvested and Ly6G and Ly6C MDSC populations were magnetically sorted. CFSE labelled T cells were then stimulated via CD3/CD28 in the presence or not of MDSCs from either saline or alum treated animals. Percent suppression was then measured. We then utilized the islet transplant model to examine the role of MDSCs on allograft rejection. First, we induced diabetes via streptozotocin injection i.p, which was done at Day -4 prior to islet transplant in a separate cohort of animals. Alum injection was then administered on day -5, -3, and -1 prior to islet transplant. To perform the islet transplant, Balb/C islets were isolated and transplanted at day 0 underneath the left kidney capsule of either alum or saline treated C57Bl/6J mice. Glucose and survival were measured
*Results: At 1, 3, and 7 days post alum administration, both the percentage of M-MDSCs and G-MDSCs were significantly higher in alum treated vs saline treated animals. Next, we examined the ability of alum vs saline elicited MDSCs to suppress T cell proliferation in vitro. We demonstrate that MDSCs from alum treated animals were able to significantly suppress CD3/CD28 T cell proliferation by 30% and that this effect was MDSC cell number dependent. To examine whether this expansion of MDSCs observed in alum treated animals could prevent rejection of fully mismatched islets, saline and alum treated C57BL/6 animals underwent islet cell transplant with Balb/C islets. Alum treated animals had significantly increased length of normoglycemia and mean survival compared to saline treated animals, 25 days vs 14 days respectively (p< 0.05).
*Conclusions: We demonstrate that alum elicited MDSCs are potent suppressors of T cell proliferation and can delay rejection of fully mismatched islet grafts up to 3 weeks compared to saline controls. These data suggest that therapeutics designed to expand MDSCs within the transplant recipient could be a useful strategy to decrease the amount of toxic induction and maintenance immunosuppressive regimens we currently employ in our transplant patients.
To cite this abstract in AMA style:Cuenca A, Feeney N, Ge J, Deng K, Fu Q, Huai G, Lee K, Rickert C, Markmann J. Alum Elicited MDSCs Delay the Rejection of Fully Mistmatched Islets in Mice [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/alum-elicited-mdscs-delay-the-rejection-of-fully-mistmatched-islets-in-mice/. Accessed April 20, 2021.
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