4.6 Article

Dual JAK2/Aurora kinase A inhibition prevents human skin graft rejection by allo-inactivation and ILC2-mediated tissue repair

Journal

AMERICAN JOURNAL OF TRANSPLANTATION
Volume 22, Issue 3, Pages 717-730

Publisher

WILEY
DOI: 10.1111/ajt.16870

Keywords

basic (laboratory) research; science; costimulation; cytokines; cytokine receptors; graft survival; immunobiology; immunosuppressant-other; immunosuppression; immune modulation; innate immunity; translational research; science; xenotransplantation

Funding

  1. National Cancer Institute [R50 CA211447]
  2. National Heart, Lung, and Blood Institute [R01 HL11879, R01 HL56067]
  3. National Institutes of Health [R37 AI34495]
  4. LLS Translational Research Grant [6462-15]
  5. [W81XWH-15-RTR-IDA]
  6. [R01 HL133823]

Ask authors/readers for more resources

AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. It reduces allograft invasion by limiting skin-homing CLA(+) donor T cells and suppresses pathogenic Th1 and Th17 cells while sparing regulatory T cells. Additionally, AJI-100 enhances human type 2 innate lymphoid cell responses for tissue repair by maintaining pSTAT5 levels and blocking interference by STAT3.
Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA(+) donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available