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1.  T helper17 Cells Are Sufficient But Not Necessary to Induce Acute Graft-Versus-Host Disease 
T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-γ after being transplanted into allogeneic recipients; however, IFN-γ was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4 T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORγt (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.
doi:10.1016/j.bbmt.2009.09.023
PMCID: PMC3876952  PMID: 19804837
Th1; Th17; BMT; GVHD
2.  LBH589 enhances T-cell activation in vivo and accelerates graft-versus-host disease in mice 
Histone deacetylase inhibitors (HDACi) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The FDA approved HDACi, Vorinostat or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of pro-inflammatory cytokines. In preclinical allogeneic transplantation models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia (GVL). LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplantation (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T-cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT, and alerts that LBH589 (Panobinostat) could have adverse effect on GVHD, and possibly on other inflammatory diseases.
doi:10.1016/j.bbmt.2012.06.002
PMCID: PMC3417119  PMID: 22698484
3.  Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo  
Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim-/- T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation.
PMCID: PMC3301434  PMID: 22432091
Bim; T cells; proliferation; apoptosis; alloantigen; GVHD; GVL; and BMT
4.  Anti-inflammatory triterpenoid blocks immune suppressive function of myeloid-derived suppressor cells and improves immune response in cancer 
Purpose
Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore it would be important to identify effective therapeutic means to modulate these cells.
Experimental Design
We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine.
Results
CDDO-Me at concentrations of 25-100 nM completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSC but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSC in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with immune-deficient SCID-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSC in peripheral blood but significantly improved the immune response.
Conclusions
CDDO-Me abrogated the immune suppressive effect of MDSC and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
doi:10.1158/1078-0432.CCR-09-3272
PMCID: PMC2840181  PMID: 20215551
Tumor immunology; myeloid-derived suppressor cells; triterpenoid
5.  PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice 
The Journal of Clinical Investigation  2009;119(12):3774-3786.
When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform θ (PKCθ), a key regulator of TCR signaling. In contrast, PKCθ was required for alloreactivity and GVHD induction. Furthermore, absence of PKCθ raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCθ-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCθ is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.
doi:10.1172/JCI39692
PMCID: PMC2786796  PMID: 19907075
6.  CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells1 
CD28 is required for the development of regulatory T cells (Tregs; CD4+CD25+Foxp3+) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4+CD25− T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4+CD25− T cells and addition of IL-2 restored Treg differentiation from CD28−/− T cells. Other common γ-chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.
PMCID: PMC2688779  PMID: 18684917

Results 1-6 (6)