HLA class II alleles and measles virus-specific cytokine immune response following two doses of measles vaccine

Abstract

Measles virus-specific T cells and the production of cytokines play a critical role in the immune response following measles immunization. To understand the genetic factors that influence variation in IFN-gamma and IL-4 responses following measles immunization and to provide insight into the factors influencing both cellular and humoral immunity to measles, we assessed associations between human leukocyte antigen (HLA) class II genes and measles-specific Th1 and Th2-type cytokine responses in peripheral blood lymphocytes from 339 children previously vaccinated with two doses of measles-mumps-rubella vaccine (MMR-II). Median values for measles-specific IFN-gamma and IL-4 secretion levels were 40.73 and 9.71 pg/ml, respectively. The global tests suggested associations between measles-specific IFN-gamma response and alleles of the DRB1 and DQB1 loci (P=0.07 and P=0.02, respectively). Specifically, DRB1*0301, *0901, and *1501 alleles were significantly associated with IFN-gamma secretion. The alleles that suggested evidence of an HLA association with IL-4 secretion were DRB1*0103, *0701, and *1101. Th1 cytokine responses and DQB1 allele associations revealed that the alleles with the strongest association with IFN-gamma secretion were DQB1*0201, *0303, *0402, and *0602. Specific alleles with a suggestive association with low measles-specific Th2 cytokine responses were DQB1*0202 and *0503. In addition, DPB1*0101, *0201, and *0601 alleles provided suggestive evidence of an HLA association with measles-induced IFN-gamma response, while DPB1*0501 was associated with an IL-4 response. These data suggest that IFN-gamma and IL-4 cytokine responses to measles may be genetically restricted in part by HLA class II genes, which in turn can restrict the cellular immune response to measles vaccine.

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: Is there evidence of the HLA effect?

“…Likewise, class II HLA-DRB1 (*0301, *0901 and *1501) and DRB1 (*0103, *0701 and *1101) alleles were associated with IFN-γ and IL-4 secretion, respectively. In addition, the DQB1 alleles with an association with IFN-γ secretion were *0201, *0303, *0402 and *0602 [26]. These previous studies could not rule out the role of other cytokines, including IL-2, IL-10 and IL-12, associated with HLA complex since they were not studied.…”

“…Prior population-based studies found associations with both class I and class II alleles and measles vaccine immune response [22][23][24]. Subsequent studies suggest the significance of HLA genes in measles virus-specific IFN-γ and IL-4 cytokine immune responses [25,26]. The class I HLA-A (*0101 and *3101) and HLA-Cw (*0303 and *0501) alleles have been significantly associated with measles virus-induced IFN-γ secretion [25].…”

“…Peripheral blood mononuclear cells (PBMC) were immediately separated from heparinized venous blood by Ficoll-Hypaque (Sigma, St. Louis, MO) density gradient centrifugation as described elsewhere [25,26]. Cells were resuspended in RPMI 1640 culture media (Celox Laboratories Inc., St. Paul, MN) containing 10% dimethyl sulfoxide (Sigma) and 20% fetal calf serum (FCS; Hyclone, Logan, UT), frozen at −80°C, and stored in liquid nitrogen.…”

“…Cells were resuspended in RPMI 1640 culture media (Celox Laboratories Inc., St. Paul, MN) containing 10% dimethyl sulfoxide (Sigma) and 20% fetal calf serum (FCS; Hyclone, Logan, UT), frozen at −80°C, and stored in liquid nitrogen. After cryopreservation, PBMC were thawed, resuspended in RPMI 1640 culture media supplemented with 10% normal human serum (NHS; Irvine Scientific, Santa Ana, CA), 100 U/ml penicillin (Sigma), and 100 g/ml streptomycin (Sigma) as previously described [25,26]. For determination of secreted IL-2 and IL-10, PBMC (4×10 5 cells/well) were cultured in duplicate with or without the Edmonston B vaccine strain of measles virus (multiplicity of infection [MOI] of 0.1) diluted in RPMI 1640 culture media supplemented with 1% NHS.…”

“…Further, we demonstrated that the HLA genes may also play a role in measles-specific cytokine responses and demonstrated significant associations with measles-induced IFN-γ and IL-4 secretion and HLA alleles [25,26]. We hypothesized that variations in IL-2, IL-10, and IL-12p40 cytokine responses to measles vaccine are associated in part with genetic polymorphisms of the HLA genes.…”