1). ILC biology and development
2). Mechanisms of tissue damage and regeneration in GVHD
3). Pathophysiology of intestinal, hepatic, and thymic GVHD
4). Mechanisms of malignant relapse after hematopoietic transplantation
Epithelial tissues are in a constant state of turnover. During inflammation, and especially after hematopoietic transplantation, the immune system can be activated, which can lead to damage of epithelium. The tissue damage after allogeneic transplantation mediated by donor T cells is referred to as graft-versus-host disease (GVHD). In response to this damage, innate immune cells can be activated to produce cytokines that promote epithelial regeneration.
Our work has shown that GVHD of the intestines can lead to loss of the intestinal stem cells necessary for maintaining and regenerating the intestinal epithelium. Likewise, innate lymphoid cells (ILCs) produce IL-22 post-transplant to stimulate epithelial regeneration and maintain intestinal barrier function. However, we have found that GVHD leads to loss of both the intestinal stem cells and ILCs necessary for epithelial recovery.
In addition to promoting intestinal barrier function, ILCs are critical for regenerating thymic epithelium and promoting immune reconstitution post-transplant, which is essential for maintaining antitumor and antimicrobial immunity. ILCs are thus working at the interface of the three greatest obstacles to successful allogeneic transplantation: GVHD, malignant relapse, and infections.
We are studying the processes of immune-mediated tissue damage and regeneration at the tissue level and at the level of the epithelial stem cells critical for tissue maintenance and regeneration. This work is important for understanding how to promote tissue regeneration post-transplant and treat GVHD without suppressing the immune system. It has important implications for understanding how solid tumors can develop in the setting of inflammation.
Biography
Alan Hanash graduated from the University of Michigan and then pursued his M.D. and Ph.D. degrees at the University of Miami, where he studied transplant immunology with Robert Levy. He then trained in internal medicine at the University of Chicago and medical oncology at Memorial Sloan Kettering Cancer Center (MSKCC), where he trained with Marcel van den Brink, studying cytokine responses in experimental bone marrow transplantation (BMT).
Dr. Hanash is now an attending physician on the Adult BMT Service at MSKCC, and his laboratory studies transplant immunology, focusing on how innate and adaptive immunity impact the intestinal epithelium. Their research has demonstrated that the intestinal stem cell compartment is targeted by donor T cells after BMT and that Interleukin-22 derived from innate lymphoid cells can protect the stem cells and stimulate epithelial regeneration. This work led to a multi-center clinical trial treating transplant patients with a novel recombinant human IL-22 dimer in order to promote intestinal recovery from graft vs. host disease.
Distinctions:
Amy Strelzer Manasevit Research Fellow
American Society of Hematology Scholar
American Society of Blood and Marrow Transplantation New Investigator
Elected to The American Society of Clinical Investigation
Director of Laboratory Science, American Society for Transplantation and Cellular Therapy Board of Directors, 2022-2025
Former Chair, American Society of Hematology Scientific Committee on Transplantation Biology and Cellular Therapies
Calafiore M, Fu YY, Vinci P, Arnhold V, Chang WY, Jansen SA, Egorova A, Takashima S, Kuttiyara J, Ito T, Serody J, Nakae S, Turnquist H, van Es J, Clevers H, Lindemans CA, Blazar BR, Hanash AM. A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury.Nature Communications. 2023 September 5;14(1):5411. PubMed PMID: 37669929; PubMed Central PMCID: PMC10480426; DOI: 10.1038/s41467-023-40993-5.
Arnhold V, Chang WY, Jansen SA, Thangavelu G, Calafiore M, Vinci P, Fu YY, Ito T, Takashima S, Egorova A, Kuttiyara J, Perlstein A, van Hoesel M, Liu C, Blazar BR, Lindemans CA, Hanash AM. Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage.JCI. 2024 Apr 1; 134(7): e155880. PubMed PMID: 38349762; PubMed Central PMCID: PMC10977993; DOI: 10.1172/JCI155880.
Takashima S, Sharma R, Chang W, Calafiore M, Fu YY, Jansen SA, Ito T, Egorova A, Kuttiyara J, Arnhold V, Sharrock J, Santosa E, Chaudhary O, Geiger H, Iwasaki H, Liu C, Sun J, Robine N, Mazutis L, Lindemans CA, Hanash AM. STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration.Nature Communications. 2025 Jan 2;16(1):138. PubMed PMID: 39746933; PMCID: PubMed Central PMC11697299. DOI: 10.1038/s41467-024-55227-5.
