Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy for a variety of malignancies, including leukemias, lymphomas, and advanced solid tumors, such as renal cell carcinoma, as well as a number of nonmalignant diseases. Although potentially curative, HSCT continues to be limited by severe morbidity and mortality caused by graft versus host disease (GVHD). One of the main topics of my laboratory is to investigate novel therapeutic strategies to mitigate GVHD in transplanted recipients using murine HSCT models. Gastrointestinal GVHD is the dominant contributor to acute GVHD-related mortality and of primary importance is to underline pathways regulating gut epithelium homeostasis. In this scenario, we have identified a novel mechanism that can potentially be translated into novel clinical strategies to prevent or ameliorate GVHD.
Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.
In the paper recently published by Dr. Alan Hanash et al. we demonstrated that Interleukine-22 (IL-22) is a critical regulator of tissue sensitivity to GVHD and a survival factor for the maintenance of intestinal stem cells (ISC) during intestinal inflammation. We found that IL-22 deficiency led to increased GVHD morbidity, mortality and pathology. IL-22 was produced post-transplant by IL-23-responsive radioresistant host-derived innate lymphoid cells (ILCs), and these cells as well as the ISCs were eliminated during GVHD. Our data also indicated that ISCs, necessary for normal epithelial maintenance, were targets of GVHD, and that IL-22 may be critical for the protection of these ISC during GVHD.(1)
Project Members
- Hanash AM, Dudakov JA, Hua G, O'Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR, van den Brink MR. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012 Aug 24;37(2):339-50.
