Abrogation of donor T cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD From GVL Meeting Abstract

Authors: Hanash, A. M.; Kappel, L. W.; Yim, N. L.; Nejat, R. A.; Goldberg, G. L.; Smith, O. M.; Rao, U. K.; Dykstra, L.; Na, I. K.; Holland, A. M.; Liu, C.; Murphy, G. F.; Leonard, W. J.; Heller, G.; van den Brink, M. R. M.
Abstract Title: Abrogation of donor T cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD From GVL
Meeting Title: 52nd Annual Meeting of the American Society of Hematology (ASH)
Abstract: Allogeneic hematopoietic transplantation is frequently the only curative therapy available to patients with hematopoietic malignancies, however transplant success continues to be limited by complications including graft vs.. host disease (GVHD) and disease relapse. Separation of GVHD from graft vs. leukemia/lymphoma (GVL) responses continues to be a major goal of experimental and clinical transplantation, and better understanding of T cell immunobiology may lead to novel strategies to accomplish this goal. Interleukin 21 (IL-21), is. a:, pro-inflammatory cytokine produced by Th17 helper T cells', and abrogation of IL-21 signaling has recently been demonstrated to reduce GVHD while retaining GVL. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL are incompletely understood. In order to characterize the effect of IL-21 on GVH. and GVL T cell responses, we compared wild type and IL-21 receptor knockout (IL-21R KO) donor T cells in a C57BL/6 into BALB/c murine MHC-mismatched bone marrow, transplant (BMT) model. Lethally irradiated BMT recipients of IL-21R KO T cells demonstrated decreased GVHD-related morbidity (p<.05) and mortality (p<.01),,and decreased histopathologic evidence of GVHD within the small intestine (p<.05). While this reduction in IL-21R KO T cell-mediated GVHD was associated with increased donor regulatory T cells two to three weeks post-BMT (p<.001), IL-21 signaling in both donor CD4 and donor CD8 T cells was found to contribute to GVHD mortality (p<.01 for CD4, p<.05 for CD8). Analysis of IL-21R expression by wild type T cells demonstrated receptor upregulation upon polyclonal activation in vitro and upon alloactivation in vivo (p<.01). However, this IL-21R upregulation was not required for in vivo alloactivation, as IL-21R KO and wild type donor T cells demonstrated equivalently greater proliferation, in allogeneic vs. syngeneic recipients (p<.001), equivalent upregulation of CD25 (p<.001), and equivalent downregulation of CD62L (p<.01 for CD8 T cells). Despite this equivalent alloactivation, IL-21R KO T cells demonstrated decreased infiltration within the small intestine (p<.05), decreased infiltration in mesenteric lymph nodes (p<.05 for CD8 T cells, p<.001 for CD4 T cells), and decreased inflammatory cytokine-producing CD4 T cells within mesenteric lymph nodes (p<.01 for IFN-g, p<.001 for TNF-a, Figure 1A). Consistent with this, transplanted IL.21R KO donor T cells demonstrated decreased expression of a4b7 integrin (LPAM, p<.05), a molecule known to be involved in homing of GVHD-mediating donor T cells to the gut. However, in contrast to the reduced inflammatory cytokine-producing CD4 T cells observed in mesenteric lymph nodes, IL-21R KO. helper T cell cytokine production was maintained in spleen (Figure 1B) and peripheral lymph nodes, and IL-21R KO T cells were able to protect recipient mice from lethality due to A20 lymphoma (p<.001). In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific, modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T cell function and GVL capacity are retained. Targeting IL-21:for therapeutic intervention is an exciting strategy to separate GVHD from GVL, and this novel approach should be considered for clinical investigation to improve transplant outcomes and prevent malignant relapse.[GRAPHICS].
Keywords: cell infiltration; disease morbidity; transplant outcome
Journal Title: Blood
Volume: 116
Issue: 21
Meeting Dates: 2010 Dec 4-7
Meeting Location: Orlando, FL
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-11-19
Start Page: 321
End Page: 322
Language: English
PROVIDER: biosis
PUBMED: 22276300
Notes: --- - Meeting Abstract: 729 - - 52nd Annual Meeting of the American-Society-of-Hematology (ASH) - Orlando, FL, USA - December 04 -07, 2010 - Amer Soc Hematol - "Source: Biosis"