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By City of Hope | March 7, 2012

Tangsheng YiThe Helix: Tangsheng, give us a brief overview of your paper.

Tangsheng Yi: Hematopoietic cell transplantation (HCT) is a curative therapy for hematopoietic malignancies, hereditary hematological disorders and refractory autoimmune diseases.  However, graft versus host disease (GVHD) remains a major obstacle for the widespread application of allogeneic HCT.  GVHD is a result of immune attack of host tissues (such as liver, gut, skin and lung) mediated by donor T cells.  These donor T cells believe that host tissues are “foreign” and attack them.  Approximately 50 percent of patients undergoing HLA-matched allogeneic HCT develop GVHD, thereby limiting the broad clinical application of allogeneic HCT.  

In our current paper, we tried to understand how aggressive donor T cells attack different host tissues and whether or not we could ameliorate or even stop this attack by blocking their inflammatory cytokine production.  We found that in mouse recipients receiving allogeneic hematopoietic cell transplantation, donor T cells can produce all three types of cytokines (Th1 cytokines, Th2 cytokines, and Th17 cytokines) to mediate tissue damage. Interestingly, we observed that each type of cytokine mediates GVHD tissue damage with distinctive tissue preference.  Th1 cytokines mainly mediate liver and gut damage; Th2 cytokines mediate lung damage; Th17 cells preferentially cause skin damage. The T cell cytokine production network is reciprocally regulated.  Genetically ablating or antibody neutralizing single subsets of Th cytokines results in augmented production of other types of Th cytokines and exacerbation of tissue-specific GVHD damage.  For example, blockade of signature Th1 cytokine IFN-γ reduced Th1-mediated liver and gut damage but exacerbated Th2- and Th17-mediated lung and skin damage.  As a conclusion, we found that the balance among Th1, Th2 and Th17 effector subsets play an important role in regulating T cell immune response and that neutralizing either Th1, Th2 or Th17 cytokines can lead to biased T cell differentiation and cause organ-specific tissue damage.

TH:  What is the significance of this research on the clinical prevention or treatment of graft versus host disease?

TY: Our study is the first to evaluate systemically the different Th cytokines in GVHD pathogenesis.  Our results clearly showed that simple T cell cytokine blockade may not be a good approach for preventing GVHD, as neutralizing Th cytokines may exacerbate organ-specific GVHD tissue damage.  This study is an important warning for cytokine-based GVHD prevention treatments.

Our observations also could have important implications for the therapy of tissue-specific GVHD.  Patients who develop organ-specific tissue damage manifestations are frequently observed in clinical HCT. Our studies indicated that this tissue-specific damage could be caused by polarized Th cytokine production. If this can be further confirmed in humans, approaches that can adjust Th differentiation might be used to treat patients with tissue specific GVHD.

TH:  What is the next step in this project?

TY:  We unexpectedly found not only that inflammatory cytokines cross-regulate each other, but inflammatory cytokines also can induce regulatory T cell (a subset of suppressor cells) expansion, which in turn restrains the inflammatory response.  We believe that this feedback loop is an important checkpoint for GVHD tissue damage, although the effect is normally overwhelmed by the influx of pathogenic cytokine producing T effector cells.  We are currently trying to understand how inflammatory cytokines induce regulatory T cell expansion mechanistically and whether or not we could ameliorate GVHD through boosting this response.

TH:  This is your third first-author paper here at City of Hope.  What have you learned about writing papers over the course of these three papers, and what has changed between your first paper and this one?

TY:  The first paper is always the most difficult one.  For my first paper, I put together all of the data and tried to organize a paper with all the data I accrued.  By the end of the writing process, I realized that some of the data were redundant, some were beyond the scope of the paper, and some data that were needed for supporting the story were missing.  For this paper and the manuscript I am preparing right now, I knew the story when it was only half-way done, and I knew what experiments I should do to make the paper into a coherent story.

TH:  What advice do you have for those students who are looking to write a first paper?

TY: In my opinion, the most important trick for paper writing is to try to write the results section of the paper as early as possible.  The paper writing itself can guide you to the experimental design and efficient completion of the research.


The following is the article mentioned in the conversation with Tangsheng Yi.

Blood, 14 July 2009, Vol. 0, No. 2009, pp. 200905219

Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft versus host disease Tangsheng Yi, Ying Chen, Lin Wang, Gong Du, Daniel Huang, Dongchang Zhao, Heather Johnston, James Young, Ivan Todorov, Dale T. Umetsu, Lieping Chen, Yoichiro Iwakura, Fouad Kandeel, Stephen Forman, and Defu Zeng*

The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, United States Children's Hospital, Harvard Medical School, Boston, MA, United States Department of Pathology, Johns Hopkins University, Baltimore, MD, United States Institute of Medical Science, University of Tokyo, Tokyo, Japan

In acute graft versus host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here, we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of IFN-{gamma} in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-{gamma} resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-{gamma} and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 is in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-{gamma}-inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.