Role of CXCR3-induced donor T-cell migration in acute GVHD

Ulrich Duffner, Bao Lu, Gerhard C. Hildebrandt, Takanori Teshima, Debra L. Williams, Pavan Reddy, Rainer Ordemann, Shawn G. Clouthier, Kathy Lowler, Chen Liu, Craig Gerard, Kenneth R Cooke, James L M Ferrara

Research output: Contribution to journalArticle

Abstract

Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8+ T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3-/- B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT. Results. Significantly higher numbers of donor CD8 + CXCR3-/- T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8 + T cells in the small bowel of BMT recipients from CXCR3 -/- donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-γ and TNF-α were equivalent between groups. Animals that received CXCR3-/- donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p <0.001). Conclusion. The migration of donor CD8+ T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality.

Original languageEnglish (US)
Pages (from-to)897-902
Number of pages6
JournalExperimental Hematology
Volume31
Issue number10
DOIs
StatePublished - Oct 1 2003
Externally publishedYes

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Graft vs Host Disease
Cell Movement
T-Lymphocytes
Bone Marrow Transplantation
Intestines
Spleen
Minor Histocompatibility Antigens
Chemokine Receptors
Liver
Small Intestine
Gastrointestinal Tract
Cytokines
Mortality

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Duffner, U., Lu, B., Hildebrandt, G. C., Teshima, T., Williams, D. L., Reddy, P., ... Ferrara, J. L. M. (2003). Role of CXCR3-induced donor T-cell migration in acute GVHD. Experimental Hematology, 31(10), 897-902. https://doi.org/10.1016/S0301-472X(03)00198-X

Role of CXCR3-induced donor T-cell migration in acute GVHD. / Duffner, Ulrich; Lu, Bao; Hildebrandt, Gerhard C.; Teshima, Takanori; Williams, Debra L.; Reddy, Pavan; Ordemann, Rainer; Clouthier, Shawn G.; Lowler, Kathy; Liu, Chen; Gerard, Craig; Cooke, Kenneth R; Ferrara, James L M.

In: Experimental Hematology, Vol. 31, No. 10, 01.10.2003, p. 897-902.

Research output: Contribution to journalArticle

Duffner, U, Lu, B, Hildebrandt, GC, Teshima, T, Williams, DL, Reddy, P, Ordemann, R, Clouthier, SG, Lowler, K, Liu, C, Gerard, C, Cooke, KR & Ferrara, JLM 2003, 'Role of CXCR3-induced donor T-cell migration in acute GVHD', Experimental Hematology, vol. 31, no. 10, pp. 897-902. https://doi.org/10.1016/S0301-472X(03)00198-X
Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P et al. Role of CXCR3-induced donor T-cell migration in acute GVHD. Experimental Hematology. 2003 Oct 1;31(10):897-902. https://doi.org/10.1016/S0301-472X(03)00198-X
Duffner, Ulrich ; Lu, Bao ; Hildebrandt, Gerhard C. ; Teshima, Takanori ; Williams, Debra L. ; Reddy, Pavan ; Ordemann, Rainer ; Clouthier, Shawn G. ; Lowler, Kathy ; Liu, Chen ; Gerard, Craig ; Cooke, Kenneth R ; Ferrara, James L M. / Role of CXCR3-induced donor T-cell migration in acute GVHD. In: Experimental Hematology. 2003 ; Vol. 31, No. 10. pp. 897-902.
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abstract = "Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8+ T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3-/- B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT. Results. Significantly higher numbers of donor CD8 + CXCR3-/- T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8 + T cells in the small bowel of BMT recipients from CXCR3 -/- donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-γ and TNF-α were equivalent between groups. Animals that received CXCR3-/- donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43{\%} vs 0{\%}, p <0.001). Conclusion. The migration of donor CD8+ T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality.",
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AU - Duffner, Ulrich

AU - Lu, Bao

AU - Hildebrandt, Gerhard C.

AU - Teshima, Takanori

AU - Williams, Debra L.

AU - Reddy, Pavan

AU - Ordemann, Rainer

AU - Clouthier, Shawn G.

AU - Lowler, Kathy

AU - Liu, Chen

AU - Gerard, Craig

AU - Cooke, Kenneth R

AU - Ferrara, James L M

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N2 - Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8+ T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3-/- B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT. Results. Significantly higher numbers of donor CD8 + CXCR3-/- T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8 + T cells in the small bowel of BMT recipients from CXCR3 -/- donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-γ and TNF-α were equivalent between groups. Animals that received CXCR3-/- donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p <0.001). Conclusion. The migration of donor CD8+ T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality.

AB - Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8+ T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3-/- B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT. Results. Significantly higher numbers of donor CD8 + CXCR3-/- T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8 + T cells in the small bowel of BMT recipients from CXCR3 -/- donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-γ and TNF-α were equivalent between groups. Animals that received CXCR3-/- donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p <0.001). Conclusion. The migration of donor CD8+ T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality.

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