The Role of PI3kγ and PI3kδ in Alloimmunity.

M. Uehara,¹ A. Jamil,¹ Z. Solhjou,¹ M. McGrath,¹ N. Banouni,¹ C. Evans,² J. Dinitto,² D. Winkler,² R. Abdi.¹

¹Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
²Infinity Pharmaceuticals, Inc, Boston.

Meeting: 2016 American Transplant Congress

Abstract number: 346

Keywords: T cells, Tolerance

Session Information

Session Name: Concurrent Session: Pathways of Allograft Rejection: Animal Models

Session Type: Concurrent Session

Date: Monday, June 13, 2016

Session Time: 4:30pm-6:00pm

Presentation Time: 4:30pm-4:42pm

Location: Room 310

We studied the role of phosphatidylinositol-3-kinases (PI3k) γ and δ pathway in alloimmunity. Generated Foxp3-GFP-PI3kγ and -PI3kδ knockout mice (C57BL/6 background) were used in heart transplant models and GVHD models. While PI3kγ^-/- and PI3kδ^-/- recipients of BALB/c hearts exhibited significant heart allograft survival prolongation compared to WT (MST: 14, 14, 7 respectively), the administration of low dose CTLA4Ig (250[mu]gon day 2) induced indefinite allograft survival of the PI3kγ^-/- recipients compared to WT (MST: >100 and 41) with a marked increase in Tregs and a reduced % of CD4⁺ and CD8⁺ Teff along with significant suppression of Th1/Th17 cytokines in the spleen and draining lymph nodes (DLN). Surprisingly, the absence of PI3kδ abrogated the effect of CTLA4Ig treatment with a marked decrease in Tregs with significant increase in CD4⁺ and CD8⁺ Teff in the spleen and DLN of the PI3kδ^-/- recipients along with significant upregulation of Th1/Th17 cytokines. Adoptive transfer of Foxp3-GFP-PI3kδ^-/- and -PI3kγ^-/- Tregs into a GVHD model showed that PI3kδ^-/- Tregs went more into apoptosis compared to PI3kγ^-/- and WT Tregs. We also examine the effect of pharmacologic inhibition of PI3k isoforms using IPI-1828 (PI3kδ selective inhibitor) and INK-055 (PI3kγ and δ inhibitor). BALB/c heart allografts were transplanted into C57BL/6 and PI3kγ^-/- mice respectively and each recipient was treated with IPI-1828 or INK-055 with or without low dose CTLA4Ig respectively. WT and PI3kγ^-/- recipients treated with IPI-1828 and PI3kγ^-/- recipients treated with IPI-1828 plus low dose CTLA4Ig showed similar allograft survivals as previous model (MST: 13, 20, >100 respectively). Furthermore, the allograft survival of WT recipients treated with INK-055 plus low dose CTLA4Ig confirmed that PI3kδ abrogates the effect of CTLA4Ig. Using double knockout recipients (CD28^-/-PI3kγ^-/- and CD28^-/-PI3kδ^-/- mice), allograft histology was observed and showed less lymphocyte infiltration in CD28^-/-PI3kγ^-/- recipient compared with CD28^-/-PI3kδ^-/-. Allograft survival data also reflected the histology data of CD28^-/-PI3kγ^-/- and CD28^-/-PI3kδ^-/- (MST: >30 and 27.5). Our data shows a differential role of PI3Kγ and PI3Kδ in Tregs homeostasis and function with significant application in the future of PI3K based therapies in solid organ transplantation.

CITATION INFORMATION: Uehara M, Jamil A, Solhjou Z, McGrath M, Banouni N, Evans C, Dinitto J, Winkler D, Abdi R. The Role of PI3kγ and PI3kδ in Alloimmunity. Am J Transplant. 2016;16 (suppl 3).

To cite this abstract in AMA style:

Uehara M, Jamil A, Solhjou Z, McGrath M, Banouni N, Evans C, Dinitto J, Winkler D, Abdi R. The Role of PI3kγ and PI3kδ in Alloimmunity. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/the-role-of-pi3k-and-pi3k-in-alloimmunity/. Accessed November 22, 2024.

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