title: The effects of interleukin 10 and interferon gamma cytokine gene polymorphisms on survival after autologous bone marrow transplantation for patients with breast cancer.
abstract: Several clinical trials evaluating the induction of autoimmune graft-versus-host disease (GVHD) after autologous bone marrow transplantation (BMT) as antitumor immunotherapy have shown that autologous GVHD is associated with increased production of interleukin (IL)-10. The induction of autologous GVHD also segregated with single nucleotide polymorphisms in the IL-10 promoter region (IL-10 -592 and IL-10 -1082 ) and with CA repeats in the first intron of the interferon (IFN)-gamma gene. Polymorphisms within these promoter regions can significantly modify the cytokine response because of differential transcription factor efficiency. This study evaluated the relationship between inheritance of polymorphisms within the IL-10 promoter and in the IFN-gamma gene and the overall survival of patients who received autologous BMT for metastatic breast cancer. Peripheral mononuclear cells from 87 women enrolled in 3 autologous BMT (plus induction of autologous GVHD) clinical trials were examined. By using a Cox proportional hazard model, trends in survival after autologous BMT were analyzed. The model included inheritance polymorphisms of IL-10 -592 , IL-10 -1082 , CA repeats within the first intron of the IFN-gamma gene, estrogen and progesterone receptor status, and stage of disease. Increased survival was significantly associated with patients having the IL-10 -592 promoter allele associated with high IL-10 production (hazard ratio, 0.23; 95% confidence interval, 0.09-0.55; P = .001). The effect of the strong IL-10 promoter allele on survival seems to be independent of the development of clinical autologous GVHD. However, decreased survival was significantly associated with patients having CA repeats associated with higher IFN-gamma transcription (hazard ratio, 2.34; 95% confidence interval, 1.21-4.54; P = .011). Inheritance of specific alleles that modify IL-10 and IFN-gamma production may have unexpected effects on the efficacy of immune-based strategies after autologous BMT. Additional studies are necessary to further define the influence of IL-10 and IFN-gamma on the immune response after BMT.
authors.affiliation: The School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Wu
authors.forename: Debra
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miura
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Thoburn
authors.forename: Deborah
authors.initials: D
authors.lastname: Armstrong
authors.forename: Georgia B
authors.initials: GB
authors.lastname: Vogelsang
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011110:Polymorphism, Genetic; D014182:Transplantation, Autologous
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma