Date: Monday, June 13, 2016
Session Name: Concurrent Session: Regulatory T Cells: Animal Models
Session Time: 2:30pm-4:00pm
Presentation Time: 3:42pm-3:54pm
Location: Room 309
CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance and T cell homeostasis. It is known that Tregs promote transplant tolerance and prevent tissue damage through multiple mechanisms including the production of IL-10 and TGF-beta. Although initial clinical trials using Tregs were promising, strategies employed to isolate and expand Tregs, however have been a limiting factor. Here, we investigated in the context of transplantation, a novel immunosuppressive approach applying NAD+-and discovered novel immunosuppressive properties that were CD4+CD25+Foxp3+ Tregs independent.
To assess NAD+ immunosuppressive properties we used a fully MHC II mismatch skin transplant mouse model. DBA/2 skin was engrafted; onto C57BL/6 mice treated with either PBS or NAD+ (30mg/day i.p.). Allograft survival and immune responses were assessed. In addition, CD4-/- and IL-10-/- deficient mice were used to demonstrate NAD+ mechanisms of action.
NAD+ treatment promoted a dramatic improvement of allograft survival (18 days vs 9 p<0.01) in parallel to a dramatic decline of CD4+CD25+Foxp3+ T cells suggesting that allograft survival was CD4+CD25+Foxp3+ T cell independent. Furthermore, our data indicated a significant increase of Th1/Th17 CD4+ T cells that are known to be two pro-inflammatory subsets. In vitro experiments indicated that in presence of NAD+, CD4+CD25LowFoxp3+ were able to differentiate into Th17 cells with a change in their transcriptional and cytokine signature profile. The results indicated an augmented expression of IL-17A and RORγt and a Th17 cell proliferation in absence of IL-23 that was mediated via P2XR and STAT3. Of particular relevance and unraveling a novel mechanism, NAD+ promoted allograft survival by skewing Th1 pro-inflammatory cells towards immunosuppressive CD 4+IFN-gamma+IL-10+ regulatory type 1 cells. More importantly, CD4-/- and IL-10-/- mice that were treated with NAD+ did not exhibit a prolonged allograft survival, suggesting that NAD+ immunosuppressive properties were mediated via CD4+ T cells and IL-10 cytokine.
Collectively, our study unravels a novel immunosuppressive therapy with intriguing and novel mechanisms with reduced side effects observed when compared to current immunosuppressive therapies that may benefit transplanted patients and beyond.
CITATION INFORMATION: Elkhal A, Rodriguez Cetina Biefer H, Uehara H, Quante M, Seyda M, Schuitenmaker J, Tullius S, Elkhal A. NAD+ Promotes Allograft Survival Independently of CD4+CD25+Foxp3+ Regulatory T Cells. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Elkhal A, Biefer HRodriguezCetina, Uehara H, Quante M, Seyda M, Schuitenmaker J, Tullius S, Elkhal A. NAD+ Promotes Allograft Survival Independently of CD4+CD25+Foxp3+ Regulatory T Cells. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/nad-promotes-allograft-survival-independently-of-cd4cd25foxp3-regulatory-t-cells/. Accessed July 8, 2020.
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