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1.  Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis and TaqI polymorphism 
Human immunology  2010;72(3):262-268.
The Vitamin D Receptor (VDR) gene encodes a transcription factor which, on activation by vitamin D, modulates diverse biological processes including calcium homeostasis and immune function. Genetic variation involving VDR shows striking differences in allele frequency between populations and has been associated with disease susceptibility including tuberculosis and autoimmunity, although results have often been conflicting. We hypothesized that methylation of VDR may be population specific and that the combination of differential methylation and genetic variation may characterise TB predisposition. We use bisulphite conversion and/or pyrosequencing to analyse the methylation status of 17 CpGs of VDR and to genotype 7 SNPs in the 3′ CpG Island (CGI 1060), including the commonly studied SNPs ApaI (rs7975232) and TaqI (rs731236). We show that for lymphoblastoid cell lines from two ethnically diverse populations (Yoruba from HapMap, n=30 and Caucasians, n=30) together with TB cases (n=32) and controls (n=29) from the Venda population of South Africa there are methylation variable positions (MVPs) in the 3′ end that significantly distinguish ethnicity (9/17 CpGs) and TB status (3/17 CpGs). Moreover methylation status shows complex association with TaqI genotype highlighting the need to consider both genetic and epigenetic variants in genetic studies of VDR association with disease.
doi:10.1016/j.humimm.2010.12.010
PMCID: PMC3955023  PMID: 21168462
VDR (vitamin D (1,25- dihydroxyvitamin D3) receptor); gene polymorphism; CpG methylation; TB (tuberculosis); ethnic differences
2.  Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells 
Human immunology  2005;66(3):222-230.
SUMMARY
The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on T cells have been well documented. Here we investigated whether human CD4+CD25+ Tregs can inhibit the pro-inflammatory properties of monocytes/macrophages. Monocytes and T cells were isolated from peripheral blood of healthy volunteers by magnetic cell separation, and co-cultured for 40 hours. Monocytes were analyzed directly for cytokine production and phenotypic changes, or re-purified and used in T cell stimulation and LPS challenge assays. Co-culture with CD4+CD25+ Tregs induced minimal cytokine production in monocytes, whereas co-culture with CD4+CD25− T cells resulted in large amounts of pro-inflammatory (TNF-α, IFN-γ IL-6) and regulatory (IL-10) cytokines. Importantly, when these CD4+CD25+ Treg-treated monocytes were re-purified after co-culture and challenged with LPS, they were severely inhibited in their capacity to produce TNF-α and IL-6 compared to control-treated monocytes. In addition, monocytes that were pre-cultured with CD4+CD25+ Tregs displayed limited up-regulation of HLA class II, CD40 and CD80, and down-regulation of CD86 compared to control-treated monocytes. This altered phenotype had functional consequences, as shown by the reduction in T cell-stimulatory capacity of Treg-treated monocytes. Together these data demonstrate that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages, thereby affecting subsequent innate and adaptive immune responses.
doi:10.1016/j.humimm.2004.12.006
PMCID: PMC3904343  PMID: 15784460
Suppression; antigen-presenting cell; rheumatoid arthritis
3.  HLA Class I: an Unexpected Role in Integrin β4 Signaling in Endothelial Cells 
Human immunology  2012;73(12):1239-1244.
The production of anti-donor antibodies to HLA class I and class II antigens following transplantation is associated with development of transplant vasculopathy and graft loss. Antibodies against HLA class I (HLA-I) molecules are thought to contribute to transplant vasculopathy by triggering signals that elicit the activation and proliferation of endothelial cells. The proximal molecular events that regulate HLA-I dependent signal transduction are not well understood. We demonstrated a mutual dependency between HLA-I and integrin β4 to stimulate signal transduction and cell proliferation. Similarly, we found that integrin β4-mediated cell migration was dependent upon its interactions with HLA-I molecules. Since integrin β4 has been implicated in angiogenesis and tumor formation, associations between integrin β4 and HLA-I may play an important role in cancer. Further characterization of interactions between HLA-I and integrin β4 may lead to the development of therapeutic strategies for the treatment and prevention of chronic allograft rejection and cancer.
doi:10.1016/j.humimm.2012.06.013
PMCID: PMC3485417  PMID: 22789625
Antibody Mediated Rejection; Endothelial Cells; HLA class I; Integrin β4; Signal Transduction
4.  Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications 
Human immunology  2012;73(12):1275-1281.
Significant progress has been made in preventing acute allograft rejection following solid organ transplantation resulting in improved allograft survival. However, long term function still remains disappointing primarily due to chronic allograft rejection. Alloimmune responses primarily defined by the development of antibodies (Abs) to donor mismatched major histocompatibility antigens during the post-transplantation period have been strongly correlated to the development of chronic rejection. In addition, recent studies have demonstrated an important role for autoimmunity including the development of Abs to organ specific self-antigens in the pathogenesis of chronic allograft rejection. Based on this, a new paradigm has evolved indicating a possible cross-talk between the alloimmune responses and autoimmunity leading to chronic rejection. In this review, we will discuss the emerging concept for the role of cellular and humoral immune responses to self-antigens in the immunopathogenesis of chronic allograft rejection which has the potential to develop new strategies for the prevention and/or treatment of chronic rejection.
doi:10.1016/j.humimm.2012.06.014
PMCID: PMC3496808  PMID: 22789626
Alloimmunity; Autoimmunity; Chronic Rejection; Th17; regulatory T-cells and Organ transplantation
5.  TARGETING THE INTRAGRAFT MICROENVIRONMENT AND THE DEVELOPMENT OF CHRONIC ALLOGRAFT REJECTION* 
Human immunology  2012;73(12):1261-1268.
In this review, we discuss a paradigm whereby changes in the intragraft microenvironment promote or sustain the development of chronic allograft rejection. A key feature of this model involves changes in the microvasculature including a) endothelial cell (EC) destruction, and b) EC proliferation, both of which result from alloimmune leukocyte- and/or alloantibody-induced responses. These changes in the microvasculature likely create abnormal blood flow patterns and thus promote local tissue hypoxia. Another feature of the chronic rejection microenvironment involves the overexpression of vascular endothelial growth factor (VEGF). VEGF stimulates EC activation and proliferation and it has potential to sustain inflammation via direct interactions with leukocytes. In this manner, VEGF may promote ongoing tissue injury. Finally, we review how these events can be targeted therapeutically using mTOR inhibitors. EC activation and proliferation as well as VEGF-VEGFR interactions require PI-3K/Akt/mTOR intracellular signaling. Thus, agents that inhibit this signaling pathway within the graft may also target the progression of chronic rejection and thus promote long-term graft survival.
doi:10.1016/j.humimm.2012.07.334
PMCID: PMC3496805  PMID: 22863981
Endothelial Cell; Microvascular Injury; Angiogenesis; Vascular Endothelial Growth Factor; Hypoxia; Allograft Rejection; Chronic Allograft Rejection; Allograft Vasculopathy
6.  Alloantibody induced platelet responses in transplants: Potent mediators in small packages 
Human immunology  2012;73(12):1233-1238.
The early histological studies of organ allografts noted platelets attached to vascular endothelium. Platelets adhere to vessels before any morphological evidence of endothelial injury. Subsequently, in vitro and in vivo experiments have demonstrated that alloantibodies can induce exocytosis of von Willebrand factor and P-selectin from endothelial cells and attachment of platelets within minutes. Platelets also adhere to and stimulate leukocytes. These interactions are increased by complement activation. After attachment platelets degranulate, releasing preformed mediators. Some chemokines stored together in platelet granules can form heteromers with synergistic functions. Heteromers containing platelet factor 4 (PF4; CXCL4) are specific to platelets and provide insights to unique platelet functions and opportunities for therapeutic intervention.
doi:10.1016/j.humimm.2012.06.011
PMCID: PMC3496803  PMID: 22789623
Platelets; antibody; monocyte; macrophage; chemokines
7.  Impact of Infection or Vaccination on Pre-existing Serological Memory 
Human immunology  2012;73(11):1082-1086.
Once established, serum antibody responses against a specific pathogen may last a lifetime. We describe a cohort of four subjects who received smallpox vaccination, and a single subject who received multiple vaccinations, with antibody levels to unrelated antigens monitored for 1–3 years. These immunizations provided the opportunity to determine if infection/vaccination and the resulting toll-like receptor stimulation would alter antigen-specific serological memory to other antigens, including bacterial toxins (tetanus, diphtheria, and pertussis) and viruses (yellow fever virus, measles, mumps, rubella, Epstein-Barr virus, and varicella-zoster virus). Our results indicate that serum IgG levels are remarkably stable and infection or vaccination are unlikely to increase or decrease pre-existing antigen-specific antibody responses.
doi:10.1016/j.humimm.2012.07.328
PMCID: PMC3478407  PMID: 22902392
antibody; vaccination; immunological memory
8.  KIR2DS2 and KIR2DS4 Promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT) 
Human immunology  2012;73(11):1109-1115.
The killer cell Ig-like receptor (KIR)-MHC class I pathway is an integral part of natural killer cell immunity, and its role in host protection from both cancer and infection is important In addition, we have shown elevated KIR2DS2 and 2DS4 expression in PBMCs of patients undergoing hematopoietic cell transplantation (HCT) [1]. Since all inhibitory KIR promoters are known to be heavily methylated, the question asked here is how and when KIR2DS2 and 2DS4 promoters had changed their methylation profile in association with HCT.
Genomic DNA, extracted from 20 KIR2DS2/4+ donor and recipient cells, was treated with sodium bisulfate that will modify the unmethylated cytosine into uracil. Sequencing chromatographs were examined for C/T double peak indicative of base conversion. A CpG island in KIR2DS2 promoter spans from −160 through +26 with 6 cytosine sites. In contrast, the KIR2DS4 promoter CpG island contains 3 cytosine sites. The noted increase of unmethylated sites was associated with increased KIR expression as measured by mRNA-cDNA Q-PCR. In addition, the frequency of unmethylated sites in the CpG island was increased after HCT. The mechanism through which hypomethylation occurs after HCT is not known but it suggests a linkage to NK clonal expansion during the process of NK education in response to transplant therapy or viral infection.
doi:10.1016/j.humimm.2012.08.013
PMCID: PMC3478408  PMID: 22939905
9.  Role of anti-vimentin antibodies in allograft rejection 
Human Immunology  2013;74(11):1459-1462.
Production of anti-vimentin antibodies (AVA) after solid organ transplantation are common. Although classically thought to be expressed mainly within the cytosol, recent evidence demonstrates that extracellular or cell surface expression of vimentin is not unusual. This review examines the evidence to assess whether AVA contribute to allograft pathology. Clinical studies suggest that AVA are associated with cardiac allograft vasculopathy in heart transplant recipients. Studies in non-human primates confirm that production of AVA after renal and heart transplantation are not inhibited by Cyclosporine. Experimental studies have demonstrated that mice pre-immunised with vimentin undergo accelerated acute rejection and vascular intimal occlusion of cardiac allografts. Adoptive transfer of hyperimmune sera containing AVA into B-cell-knock-out mice caused accelerated rejection of allografted hearts, this is clear evidence that antibodies to vimentin accelerate rejection. AVA act in concert with the alloimmune response and AVA do not damage syngeneic or native heart allografts. Confocal microscopy of allografted organs in vimentin immunised mice shows extensive expression of vimentin on endothelial cells, apoptotic leukocytes and platelet/leukocyte conjugates, co-localising with C4d. One explanation for the ability of AVA to accelerate rejection would be fixation of complement within the graft and subsequent pro-inflammatory effects; there may also be interactions with platelets within the vasculature.
doi:10.1016/j.humimm.2013.06.006
PMCID: PMC3820003  PMID: 23777935
AMR, antibody mediated rejection; AVA, anti-vimentin antibodies; CFA, complete Freund’s adjuvant; HMEC, human microvascular endothelial cells; MMF, mycophenolate mofetil; PAF, platelet activating factor
10.  THE INFLUENCE OF HLA CLASS I ALLELES AND THEIR POPULATION FREQUENCIES ON HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 CONTROL AMONG AFRICAN AMERICANS 
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
doi:10.1016/j.humimm.2011.01.003
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
11.  Gene expression profiling of the donor kidney at the time of transplantation predicts clinical outcomes 2 years after transplantation 
Human immunology  2010;71(5):451-455.
We have previously demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short-term post-transplantation clinical outcomes. Now we provide a post hoc analysis of our earlier data in the light of longer clinical follow-up. A total of 75 consecutively performed renal allografts were analyzed for gene expression of proinflammatory molecules, inflammation-induced adhesion molecules, and antiapoptotic genes expressed 15 minutes after vascular reperfusion to determine whether this analysis can aid in predicting long-term quality of renal function, proteinuria, graft loss, and death-censored graft. We have built predictive models for proteinuria (area under the curve = 0.859, p = 0.0001) and graft loss (area under the curve = 0.724, p = 0.027) 2 years post-transplantation using clinical variables in combination with intragraft gene expression data of tumor necrosis factor–α, interleukin-6, CD40, CD3, and tumor necrosis factor–α, Bcl-2, and interferon-γ, respectively. This post hoc analysis demonstrates that hypothesis-driven, targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post-transplantation clinical outcomes.
doi:10.1016/j.humimm.2010.02.013
PMCID: PMC3776421  PMID: 20156509
Renal transplantation; PCR; Prediction; Proteinuria; Graft loss
12.  In Contrast to HIV, KIR3DS1 Does Not Influence Outcome In HTLV-1 Retroviral Infection 
Human Immunology  2012;73(8):783-787.
While most carriers of human T-cell leukemia virus type 1 (HTLV-1) remain asymptomatic throughout their lifetime, infection is associated with the development of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact parameters that determine these outcomes are unknown but are believed to include host genetic factors that control the immune response to infection. Host response to fellow retroviridae member HIV is influenced by the expression of members of the Killer Immunoglobulin Receptor (KIR) family including KIR3DS1. In this study we examined the association of KIR3DS1 with the outcome of HTLV-1 infection in three geographically distinct cohorts (Jamaican, Japanese and Brazilian). Despite increased prevalence of KIR3DS1 in the HAM/TSP patients of the Jamaican cohort, we found no evidence for a role of KIR3DS1 in influencing control of proviral load or disease outcome. This suggests that unlike HIV, KIR3DS1-mediated regulation of HTLV-1 infection does not occur, or is ineffective.
doi:10.1016/j.humimm.2012.05.006
PMCID: PMC3402611  PMID: 22609443
13.  Cellular and molecular determinants for the development of natural and induced regulatory T cells 
Human immunology  2012;73(8):773-782.
Regulation of immune responses to self and foreign antigens is critically dependent on suppressive CD4+ T cells characterized by expression of Foxp3. The large majority of regulatory T (Treg) cells develop in the thymus as a stable suppressive lineage. However, under the proper physiological conditions, conventional peripheral CD4+ T lymphocytes also develop into Treg cells, particularly in the gut mucosa and inflammatory tissue sites. This review will focus on our current understanding of the immunological and molecular signals controlling the development of thymic derived natural (n)Treg and peripheral converted induced (i)Treg cells. Given the importance of Foxp3 in the development of these cells, particular attention is placed on how such signals are integrated to induce and maintain the expression of this signature transcriptional regulator of Treg cells.
doi:10.1016/j.humimm.2012.05.010
PMCID: PMC3410644  PMID: 22659217
14.  HLA-G polymorphisms and soluble HLA-G protein levels in women with recurrent pregnancy loss from Basrah province in Iraq 
Human immunology  2012;73(8):811-817.
HLA-G is a nonclassical, class I major histocompatibility complex (MHC) gene that exhibits immunomodulatory properties and likely plays a role in the maintenance of successful pregnancy. In this study, we investigated the role of HLA-G polymorphisms on risk for recurrent pregnancy loss (RPL) and on circulating levels of soluble (s)HLA-G in Iraqi women. DNA and plasma were obtained from blood samples collected at 9 to 12 weeks gestation from 50 women with RPL and 50 healthy pregnant women in Basrah province, Iraq. As measured by ELISA, median sHLA-G levels were significantly lower in the RPL cases compared to healthy controls (21.4 vs. 38.8 U/ml, respectively; P = 0.025), and decreased with increasing maternal age (P = 0.0051). However, HLA-G allele and haplotype frequencies did not differ significantly between cases and controls (P values ≥ 0.12 for all tests). In contrast, homozygosity for the C allele (CC) at a tri- allelic promoter polymorphism, −725C/G/T, was associated with lower concentrations of sHLA- G compared to the CG or CT genotypes (median levels 21.1 vs. 40.1 vs. 42.6 U/ml, respectively; P = 0.0089). These results demonstrate that HLA-G genotype influences circulating sHLA-G levels during pregnancy but is not significantly associated with risk of RPL.
doi:10.1016/j.humimm.2012.05.009
PMCID: PMC3437257  PMID: 22651916
HLA-G; recurrent pregnancy loss; soluble HLA-G; HLA-G genotype
15.  Role of complement and NK cells in antibody mediated rejection 
Human immunology  2012;73(12):1226-1232.
Despite extensive research on T cells and potent immunosuppressive regimens that target cellular mediated rejection, few regimens have been proved to be effective on antibody-mediated rejection (AMR), particularly in the chronic setting. C4d deposition in the graft has been proved to be a useful marker for AMR; however, there is an imperfect association between C4d and AMR. While complement has been considered as the main player in acute AMR, the effector mechanisms in chronic AMR are still debated. Recent studies support the role of NK cells and direct effects of antibody on endothelium cells in a mechanism suggesting the presence of a complement-independent pathway. Here, we review the history, currently available systems and progress in experimental animal research. Although there are consistent findings from human and animal research, transposing the experimental results from rodent to human has been hampered by the differences in endothelial functions between species. We briefly describe the findings from patients and compare them with results from animals, to propose a combined perspective.
doi:10.1016/j.humimm.2012.07.330
PMCID: PMC3728655  PMID: 22850181
16.  Allostimulatory activity of BM-derived plasmacytoid DC is independent of IDO but regulated by ICOSL expression 
Human immunology  2009;70(5):313-320.
We investigated the role of two key immunoregulatory molecules, indoleamine dioxygenase (IDO) and inducible costimulator ligand (ICOSL), in determining the function of bone marrow (BM)-derived plasmacytoid (p)DC, that offer potential for therapy of allograft rejection. pDC generated from BM of wild-type (WT) or IDO knockout (KO) C57BL/6 mice were used to stimulate T cell proliferation and IFNγ production in response to alloAg via the direct or indirect pathways. In some experiments, pDC were first activated by exposure to CpG ± CTLA4Ig for IDO induction via B7 ligation. Although IDO KO pDC induced enhanced T cell responses compared to WT pDC, use of the IDO inhibitor 1-methyl-tryptophan (1-MT) showed that the inferior stimulatory capacity of WT pDC was not due to production of functional IDO, even under IDO-inducing conditions. DNAX-activating protein of 12kDa (DAP12), that inhibits functional IDO expression, was expressed in BM-pDC. DAP12 silencing increased the T cell stimulatory capacity of WT pDC, but only in the presence of 1-MT. Compared with WT pDC, activated IDO KO DC expressed much lower levels of ICOS-L. Moreover, when ICOSL was blocked on WT pDC, T cell proliferation resembled that induced by IDO KO pDC, and IL-10 secretion in MLR was markedly decreased. These findings implicate ICOSL-induced IL-10, but not IDO in regulation of BM-derived pDC function.
doi:10.1016/j.humimm.2009.01.021
PMCID: PMC3721197  PMID: 19208362
Dendritic cells; indoleamine dioxygenase; T cells; DNAX-activating protein of 12kDA; inducible costimulator ligand
17.  Myeloid-derived suppressor cells: Natural regulators for transplant tolerance 
Human immunology  2010;71(11):1061-1066.
Myeloid derived suppressor cells (MDSC) contribute to the negative regulation of immune response in cancer patients. This review summarizes results on important issues related to MDSC biology, including expansion and activation of MDSC, phenotype, and subsets as well pathways and different mechanisms by which these cells exert their suppressive effect. Recent observations suggesting that MDSC may have roles in transplant tolerance are presented. Although therapeutic targeting and destruction of MDCS is of primary interest in cancer patients, in transplantation it will instead be necessary to induce, expand, and activate these cells; thus current possibilities for in vitro generation of MDSC are also discussed.
doi:10.1016/j.humimm.2010.08.001
PMCID: PMC3713408  PMID: 20705113
Myeloid derived suppressor cells; Organ transplantation; Tolerance
18.  Characterization of the HLA-C*07:01:01G allele group in European and African-American cohorts 
Human Immunology  2012;73(7):715-719.
The HLA-C*07:01:01G allele group consists of three nonsynonymous alleles, C*07:01:01, C*07:06 and C*07:18, plus C*07:01:02, which is synonymous to C*07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. In the present study, we fully characterized C*07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C*07:01:01G is predominantly represented by C*07:01:01 (94.4%), whereas C*07:01:02 (1.1%) and C*07:18 (4.5%) were detected relatively infrequently. In African Americans C*07:18 (42.4%) showed a high frequency similar to that of C*07:01:01 (44.7%) whereas C*07:06 was detected at a low frequency (4.7%). C*07:06 was found exclusively on B*44:03 carrying haplotypes in both ethnic groups, but C*07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C*07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If C*07:01:01G subtypes prove to bear divergent functional significance, it would be necessary to include these subtypes in routine HLA-C typing for clinical transplantation and disease association studies.
doi:10.1016/j.humimm.2012.04.021
PMCID: PMC3377779  PMID: 22548719
HLA-C locus; allele diversity; C*07:01:01G; allele combination; sequence-based typing (SBT)
19.  Identification of HLA-A24 restricted CD8+ Cytotoxic T-Cell Epitopes Derived from Mammaglobin-A, A Human Breast Cancer Associated Antigen 
Human immunology  2011;73(1):11-16.
Human breast cancer associated antigen, Mammaglobin-A (Mam-A), potentially offers a novel therapeutic target as breast cancer vaccines. In this study, we define the CD8+ CTL response to Mam-A derived candidate epitopes presented in the context of HLA-A24 (A*2402). HLA-A24 has a frequency of 72% in Japanese, 27% in Asian-Indian and 18% in Caucasian populations. Using HLA-binding prediction algorithm we identified seven HLA-A24 restricted Mam-A-derived candidate epitopes (MAA24.1–7). Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-A2402 (T2.A24) indicated that MAA24.2 (CYAGSGCPL) and MAA24.4 (ETLSNVEVF) have the highest HLA-A24 binding affinity. Further, two CD8+ CTL cell lines generated in vitro against T2.A24 cells individually loaded with Mam-A-derived candidate epitopes showed significant cytotoxic activity against MAA24.2 and MAA24.4. In addition, the same CD8+ CTL lines lysed the HLA-A24+/Mam-A+ stable transfected human breast cancer cell line AU565 and MDA-MB-361. However, these CTLs had no cytotoxicity against HLA-A24−/Mam-A+ and HLA-A24+/Mam-A− breast cancer cell lines. In summary, our results define HLA-A24-restriced, Mam-A-derived, CD8+ CTL epitopes which can potentially be employed for Mam-A-based breast cancer vaccine therapy to breast cancer patients with HLA-A24 phenotype.
doi:10.1016/j.humimm.2011.10.017
PMCID: PMC3674634  PMID: 22074997
Vaccine; HLA-A24; CD8 T cell; Mammaglobin-A; Breast Cancer
20.  Replication of Associations between Cytokine and Cytokine Receptor Single Nucleotide Polymorphisms and Measles-Specific Adaptive Immunophenotypic Extremes 
Human Immunology  2012;73(6):636-640.
Our objective was to replicate previously reported associations between cytokine and cytokine receptor SNPs and humoral and CMI (cell-mediated immune) responses to measles vaccine. All subjects (n=758) received two doses of MMR (measles/mumps/rubella) vaccine. From these subjects, candidate cytokine and cytokine receptor SNPs were genotyped and analyzed in 29–30 subjects falling into one of four “extreme” humoral (Abhigh/low) and CMI (CMIhigh/low) response quadrants. Associations between seven SNPs (out of 11 in the discovery study) and measles-specific neutralizing antibody levels and IFN-γ ELISPOT responses were evaluated using chi-square tests. We found one replicated association for SNP rs372889 in the IL12RB1 gene (P=0.03 for AbhighCMIhigh versus AblowCMIlow). Our findings demonstrate the importance of replicating genotypic-phenotypic associations, which can be achieved using immunophenotypic extremes and smaller sample sizes. We speculate that IL12RB1 polymorphisms may affect IL-12 and IL-23 binding and downstream effects, which are critical cytokines in the CMI response to measles vaccine.
doi:10.1016/j.humimm.2012.03.015
PMCID: PMC3368081  PMID: 22504412
Measles immunity; SNP; Cytokine Receptor; IL12RB1; Replication Study
21.  The TBX21 transcription factor T-1993C polymorphism is associated with decreased IFN-γ and IL-4 production by primary human lymphocytes 
Human Immunology  2012;73(6):673-676.
Summary
T-bet is a transcription factor that drives the Th1 immune response primarily through promoting expression of the IFN-γ gene. Polymorphisms in the T-bet gene, TBX21, have been associated with immune-mediated diseases such as asthma and systemic sclerosis. We found that the TBX21 promoter polymorphism T-1993C is associated with a significant decrease in IL-4 and IFN-γ production by stimulated primary human lymphocytes from healthy participants.
doi:10.1016/j.humimm.2012.03.005
PMCID: PMC3368090  PMID: 22521571
TBX21; T-bet; single nucleotide polymorphism; cytokine; Th1/Th2 cells
22.  Independence of Measles-Specific Humoral and Cellular Immune Responses to Vaccination 
Human Immunology  2012;73(5):474-479.
With a larger, independent cohort and more sophisticated measures, we sought to confirm our work that indicated independence of humoral and cellular immunity following measles vaccination. We recruited an age-stratified random cohort of 764 healthy subjects from all socio-economic strata, all with medical-record documentation of two age-appropriate doses of measles-containing vaccine. We quantified measles-specific neutralizing antibody levels and assayed the IFN-γ ELISPOT response to measles virus. We also measured secreted cytokines from the PBMCs in response to measles virus by performing enzyme-linked immunosorbent assays as secondary measures of cellular immune status. The median antibody level and median IFN-γ ELISPOT response were 844 mIU/mL (IQR: 418 to 1,752) and 36 (IQR: 13.00 to 69.00) spot-forming cells (per 2×105 PBMCs), respectively. We found only a very weak and negative correlation [Spearman’s rs or rho of −0.090 (95 percent confidence interval −0.162 to −0.018)]. We found a similar lack of quantitatively important correlations between the neutralizing antibody level and any of the secondary measures. Our data confirm the independence of humoral and cellular immune responses after the second dose of measles vaccination. As researchers pursue novel measles vaccine and measles vaccine delivery systems, they must not infer that humoral responses predict cellular responses.
doi:10.1016/j.humimm.2012.02.016
PMCID: PMC3338862  PMID: 22406060
Measles Vaccine; Immunity, Humoral; Immunity, Cellular; Antibody Formation; Cytokines
23.  Immune responses to self-antigens in asthma patients: Clinical and immuno-pathological implications 
Human Immunology  2012;73(5):511-516.
Asthma leads to chronic airway inflammation that shares pathological features of chronic rejection after lung transplantation. Due to significant role of autoimmunity in chronic rejection, we hypothesized that immunity to self-antigens may also be present in asthma. The goal was to define immune responses to self-antigens in patients with asthma. Blood and clinical data were collected from 99 asthmatics and 60 controls. Serum was analyzed for antibodies (Abs) to Collagen V (ColV) by ELISA and correlated with disease severity. Asthmatics' sera were tested in human protein array to determine immune responses to other self-antigens. Asthmatics had higher concentration of Abs to ColV (predominantly IgG isotype) compared to control (p < 0.01). These Abs correlated with severe asthma (p<0.01) and corticosteroid use (p=0.032). Additionally, Abs to novel self-antigens epidermal group factor receptor (EGFr), activin A type 1 receptor, and alpha-catenin (α-catenin) were detected in asthmatics. We conclude that Abs to self-antigens (ColV, EGFr, Activin A type 1 receptor, and α-catenin) are present in asthmatics sera correlating with clinical disease. Epithelial damage from airway inflammation during asthma may result in exposure of cryptic self-antigens or their determinants resulting in immune response to self-antigens and these may contribute to pathogenesis of asthma.
doi:10.1016/j.humimm.2012.02.010
PMCID: PMC3338898  PMID: 22386692
Asthma; Autoimmunity; Collagen V; epidermal growth factor receptor; Activin A type 1 receptor; alpha catenin
24.  Lymphocyte activation markers may predict the presence of donor specific alloreactivity in pediatric living related liver transplant recipients 
Human immunology  2011;72(5):392-397.
This is an observational study with the primary objective to measure donor-specific immune responses by pediatric liver transplant (LT) recipients, using cell surface expression of lymphocyte activation markers and cytokine secretion in mixed lymphocyte reactions. The secondary objective was to demonstrate possible mechanism(s) involved in those who demonstrated donor-specific hyporesponsiveness. Study participants included 17 recipients, their respective parental donors, the non-donor parent, as well as unrelated third party individuals. Within the CD4+ population, two distinct patterns of CD69 and CD71 expressions were observed: recipients who had a lower percentage of CD4+CD69+ and CD4+CD71+ cells after donor versus non-donor stimulation (therefore a donor/non-donor ratio <1); and recipients who had a higher percentage of CD4+CD69+ and CD4+CD71+ cells after donor versus non-donor stimulation (therefore a donor/non-donor ratio ≥1). Eight recipients had the above defined ratio of <1, with significantly decreased interferon-γ secretion after donor versus non-donor stimulation. CD4+CD25hi˙CD127– regulatory T cells from these eight recipients suppressed donor and non-donor cell induced proliferation. Suppression of proliferation was partially abrogated by interleukin-2. In conclusion, CD69 and CD71 cell surface expression with interferon-γ secretion can be used to identify two distinct populations in pediatric LT recipients. Both active regulation and anergy underlie donor specific hyporesponsiveness.
doi:10.1016/j.humimm.2011.02.003
PMCID: PMC3635832  PMID: 21315129
Lymphocyte activation; Immune reactivity; Liver transplantation
25.  Sequence variations at the HLA-linked olfactory receptor cluster do not influence female preferences for male odors 
Human immunology  2010;71(1):100-103.
We previously reported that paternally-inherited human leukocyte antigen (HLA) alleles are a template for women's preference for male odors (P = 0.0007). However, it has been suggested that sequence variation in a nearby olfactory receptor (OR) cluster on chromosome 6p influences smell preference. To determine if the HLA-linked OR genes contribute to previously observed HLA-mediated behaviors, we use the odor preference data from our earlier study in combination with a new resequencing study of four functional HLA-linked OR genes in the same subjects. Our results indicate that OR alleles in the genes surveyed are not in linkage disequilibrium (LD) with HLA variation and do not explain the previous findings of HLA-associated odor preference.
doi:10.1016/j.humimm.2009.10.004
PMCID: PMC3631539  PMID: 19833159

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