Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease.
The incidence and severity of acute graft-versus-host disease (GVHD) after allogeneic transplantation using peripheral blood progenitor cells mobilized by granulocyte colony-stimulating factor (G-CSF) appear to be no worse than those after bone marrow transplantation, despite the presence of large numbers of T cells in the donor infusion. Experimental studies have shown that type-1 T cells (secreting interleukin-2 [IL-2] and interferon-gamma) mediate acute GVHD, whereas type-2 T cells (secreting IL-4 and IL-10) can prevent acute GVHD. We tested the hypothesis that G-CSF modulates T-cell function toward a type-2 response and thus reduces the severity of acute GVHD. B6 mice were injected with G-CSF or diluent for 4 days, and their splenic T cells were stimulated in vitro with alloantigen or mitogen in the absence of G-CSF. T cells from G-CSF-treated mice showed a significant increase in IL-4 production, with a simultaneous decrease in IL-2 and interferon-gamma production in response to both stimuli. We also examined the effect of G-CSF pretreatment of donors in a GVHD model (B6-->B6D2F1). Survival was significantly improved in recipients of G-CSF-treated donors. Concanavalin-A-induced cytokine production at day 13 after transplantation also showed an increase in IL-4 along with a decrease in IL-2 and IFN-gamma production by splenocytes from recipients of G-CSF-treated bone marrow and T cells. These data show that pretreatment of donors with G-CSF polarizes donor T cells toward the production of type-2 cytokines, which is associated with reduced type-1 cytokine production and reduced severity of acute GVHD.
Division of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
L
L
Pan
J
J
Delmonte
C K
CK
Jalonen
J L
JL
Ferrara
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011292:Premedication; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000637:transplantation; D018418:Th2 Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D014019:Tissue Donors
D007155:Immunologic Factors; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4