title: Alleviation of chronic GVHD in mice by oral immuneregulation toward recipient pretransplant splenocytes does not jeopardize the graft versus leukemia effect.
abstract: Chronic graft versus host disease (cGVHD) is the result of an immune-mediated attack by transplanted donor lymphocytes, entailing inflammatory damage to host target organs. Clinically, the post-bone marrow transplantation (BMT) graft versus leukemia (GVL) effect may be associated with GVHD. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of cGVHD in a murine model. To evaluate whether amelioration of cGVHD in mice by induction of oral immune regulation in donors toward recipient pretransplant lymphocyte antigens is associated with attenuation of the GVL effect donor B10.D2 mice were fed with Balb/c splenocytes, B10.D2 splenocytes, bovine serum albumin (BSA), or regular chow, every other day for 10 days. Subsequently, transplantation of 2 x 10(7) splenocytes from donor B10.D2 mice to recipient Balb/c mice was undertaken, followed by inoculation of 3 x 10(3) BCL-1 leukemia on the day of BMT. Control groups were fed identically without leukemia inoculation. Mice were followed for survival and leukemia progression. Induction of tolerance was assessed by a mixed lymphocyte reaction (MLR). Cutaneous GVHD was assessed macroscopically. To elucidate the mechanism of any observed effect, serum interferon (IFN), interleukin (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme-linked immunosorbent assay and flow cytometry analysis for CD4+, CD8+, and NK1.1+ lymphocyte subpopulations was performed. There was no significant difference in leukemia progression manifested by survival or white blood cell counts of orally immune-regulated mice compared with control animals. Cutaneous cGVHD was significantly ameliorated in Balb/c mice transplanted from tolerized B10.D2 mice. This effect was associated with a significant reduction in the mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against Balb/c target splenocytes; significantly decreased serum IFN-gamma and IL-2; increased serum IL-12 levels; increased peripheral NK1.1+ cells; and CD4+/CD8+ lymphocyte ratio. Oral tolerization of BMT donors toward recipient antigens ameliorates cGVHD without hampering the GVL effect.
authors.affiliation: Liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
authors.forename: Maya
authors.initials: M
authors.lastname: Margalit
authors.forename: Meir
authors.initials: M
authors.lastname: Ohana
authors.forename: Israel
authors.initials: I
authors.lastname: Gotsman
authors.forename: Elazar
authors.initials: E
authors.lastname: Rabbani
authors.forename: Dean
authors.initials: D
authors.lastname: Engelhardt
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002457:Cell Extracts / Q000276:immunology / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000187:drug effects* / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D002457:Cell Extracts; D016207:Cytokines