Human Lymphocyte Antigen Alleles Research Articles

Therapeutic Vaccine Against HIV, Viral Variability, Cytotoxic T Lymphocyte Epitopes, and Genetics of Patients.

The scientific and medical community is seeking to cure HIV. Several pathways have been or are being explored including therapeutic vaccination. Viroimmunological studies on primary infection as well as on elite controllers have demonstrated the importance of the cytotoxic CD8 response and have mainly oriented research on vaccine constructs toward this type of response. The results of these trials are clearly not commensurate with the hope placed in them. Might there be one or more uncontrolled variables? The genetics of patients need to be taken into consideration, especially their human lymphocyte antigen (HLA) alleles. There is a need to find a balance between the conservation of cytotoxic T lymphocyte (CTL) epitopes and presentation by HLA alleles. The pathway is a narrow one between adaptation of the virus to HLA I restriction and the definition of conserved proviral CTL epitopes presentable by HLA I alleles. It is likely that the genetics of patients will need to be considered for HIV-1 vaccine studies and that multidisciplinary collaboration will be essential in this field of infectious diseases.

Soluble Recombinant CMVpp65 Spanning Multiple HLA Alleles for Reconstitution of Antiviral CD4+ and CD8+ T-Cell Responses After Allogeneic Stem Cell Transplantation

The reactivation of the human cytomegalovirus (CMV) can be prevented or controlled by the adoptive transfer of ex vivo expanded donor-derived CMV-specific T lymphocytes. Several methods for expansion and adoptive transfer of CMV-specific T cells have been developed using either defined CMV peptides or peptide pools for antigen-specific T-cell stimulation. The majority of studies have focused on the lower matrix protein (pp65) and the immediate-early protein-1 (IE-1) of CMV as immunodominant targets. We investigated the behavior of secretory CMVpp65 (sCMVpp65) with respect to its capacity to stimulate pp65-specific T cells independently of human lymphocyte antigen (HLA) type and even in donors unresponsive to the immunodominant HLA-A*0201-restricted CMVpp65495-503 peptide. To facilitate the eukaryotic expression and isolation procedures, we constructed an HLA-A*0201/CMVpp65 fusion protein that is secreted into the supernatant of human embryonic kidney 293 (HEK293) cells. CMV-specific CD4 and CD8 T cells generated by culturing unfractionated peripheral blood mononuclear cells in the presence of recombinant sCMVpp65 did not differ in function with regard to cytotoxicity and interferon-gamma (IFN-gamma) production compared with cytotoxic T cells induced using the well-studied HLA-A*0201-restricted CMVpp65495-503 peptide. We demonstrated that polyclonal CMV-specific T cells could be generated from CMV-seropositive individuals expressing HLA alleles for which no immunogenic epitopes have been identified so far. The production of recombinant sCMVpp65 can easily be adapted to good manufacturing practice conditions and can be used to generate large numbers of immunogenic pathogen-derived proteins for therapeutic applications.

Vaccination against drug resistance in HIV infection

HIV-1 resistance to currently employed antiretroviral drugs and drug-associated adverse reactions and toxicity point to a need for additional measures to control HIV-1 replication in HIV-infected patients. The immune system of HIV-infected individuals mount an immune response against the regions harboring drug-resistance mutations, sometimes stronger than that against the parental wild-type sequences. A potent cross-reactive immune response against drug-resistant pol proteins can suppress the replication of drug-escaping HIV. This suggests the possibilty for a vaccination against existing and anticipated drug-resistant HIV variants. If successful, therapeutic vaccines against drug resistance would ease the therapeutic modalities and limit the spread of drug-resistant HIV. A better understanding of the complex interactions between patterns of drug-resistance mutations, immune responses against these mutations and their antigen presentation by particular human lymphocyte antigen alleles could help to tailor these vaccines after new drugs/new mutations. In this review, we describe the developments in the field of immunization against mutations conferring drug resistance and evaluate their prospects for human vaccination.

HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1

BackgroundVery little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression.Methods and FindingsIn a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection.ConclusionsThese data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10(-5)) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

B and C hepatitis viruses, HLA-DQ1 and -DR3 alleles and autoimmunity in patients with hepatocellular carcinoma

Background/Aims : Hepatitis B and C involvement in hepatocellular carcinoma has been well established, but as yet not that of the human lymphocyte antigen (HLA) complex. To study viral, HLA and tumour interrelationships, 105 patients were evaluated for prevalence of viral markers and 161 patients, including 99 of the previous ones, for HLA allele frequency; the other 52 patients served as controls. Methods : Immunoassays, molecular assays, microlymphocytotoxicity. Results : Positivity for hepatitis B surface antigen and/or hepatitis C antibodies in 89% cirrhotic, 44% non-cirrhotic vs. 92% control patients (cirrhotic; all hepatitis C antibody positives were viraemic). Recurrent HLA alleles: HLA-Cw7 and -DQ1 in cirrhotic and control patients, HLA-Cw7, -B8 and -DR3 in non-cirrhotic patients compared with healthy controls ( P c=0.0000074, 0.000025, 0.0025, 0.00027 and 0.043, respectively). Conclusions : Viral data suggest a high chronic infection rate for cirrhotic patients. Recurrent HLA-Cw7 is compatible with natural killer cell activity inhibition to virus-infected and tumour cells by HLA C molecules. Recurrent HLA-DQ1 and -DR3 suggest the existence of an autoimmune condition with cell destruction in cirrhotic and without cell destruction in non-cirrhotic patients as a consequence of autoreactive DQ-restricted T-helper (Th)1 and DR-restricted Th2 cells response, respectively. HLA-B8-DR3 linkage disequilibrium was possible. Thus, autoimmunity may have contributed to hepatocellular carcinoma development in these patients.

Heterophile anti-mouse immunoglobulin antibodies may interfere with cytokine measurements in patients with HLA alleles protective for type 1A diabetes.

Wilson and coworkers (Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA: Extreme Th1 bias of invariant V alpha24J alpha Q T-cells in type 1 diabetes. Nature 391:177-181, 1998) have recently reported raised serum levels of interleukin-4 (IL-4) in anti-islet autoantibody-positive first-degree relatives of patients with type 1A diabetes who did not progress to diabetes. Protection from diabetes has been noted for several human lymphocyte antigen (HLA) alleles, such as HLA DR2-DQA1*0102-DQB1*0602. We, therefore, wanted to determine whether this cytokine phenotype was associated with HLA genes protective for type 1A diabetes. We used a two-site fluoroimmunoassay with the same monoclonal antibodies as those reported by Wilson et al. Using this assay, we have found evidence for human heterophile antibodies mimicking serum IL-4: all serum IL-4 reactivity was lost if mouse serum or mouse immunoglobulin were added to the assay; serum IL-4 activity was bound and then eluted by protein A/G chromatography; and levels of anti-mouse antibodies correlated with apparent serum IL-4. This pseudo-IL-4 activity was found in a subset of control subjects, patients with type 1A diabetes, and their relatives and was primarily associated with specific HLA alleles protective for type 1A diabetes (e.g., DQB1*0602). After adjustment for HLA, positive levels of heterophile antibodies were not associated with protection from diabetes. The confounding effect of protective HLA alleles associated with heterophile antibodies could explain the previously reported association between raised serum IL-4 and protection from type 1A diabetes. The mechanism by which specific DQ alleles protect from diabetes and are associated with increased heterophile antibodies is currently unknown.

Induction of Antigen-Specific Cytotoxic T Lymphocytes in Humans by a Malaria DNA Vaccine

CD8+ cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8+ T cell responses. Malaria-naïve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8+ T cell-dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naïve humans of the induction of CD8+ CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same individual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.

Mechanisms for induction of autoimmunity in humans.

The triggering or immunogenic stimulus for human autoimmune diseases is unknown. It is not even known whether the stimulus is endogenous, i.e. truly "self" or exogenous, "non-self". Many autoimmune diseases are human lymphocyte antigen (HLA)-associated and demonstrate linkage to the HLA chromosome in family investigations. For most of these diseases, evidence is strong that the association is directly dependent on specific HLA class I or II molecules rather than on other genes located in the HLA region. Since HLA polymorphic HLA molecules have so far only been shown to have two distinct functions, both of which are immunological, a HLA association supports the notion that a particular disease is autoimmune. Furthermore, an association to a specific HLA allele implies that the immunogenic stimulus for autoimmunity would be one specific HLA-binding peptide and that, at least initially, autoimmunity is dependent on the reactivity of one or a limited number of potentially autoaggressive T cell clones. These findings are encouraging and formin the basis for future preventive measures. One current theory is that autoimmune disease is precipitated by an environmental agent, such as a viral infection. Several different mechanisms to explain how a viral infection could induce autoimmune disease in humans are described and one specific example is presented for a virus-induced autoimmune disease in humans. The question of whether ITP could also be dependent on such a mechanism is briefly discussed.

Association of Human Lymphocyte Antigens with Obstructive Airways Disease after Bone Marrow Transplantation

BACKGROUND: Obstructive airways disease (OAD) is a known complication of allogeneic bone marrow transplantation. The etiology of OAD is unknown but is probably multifactorial. The identification of a significant human lymphocyte antigen (HLA) association with the development of OAD might offer some insight into its pathogenesis and serve as a marker to identify prospectively patients at risk for developing OAD.OBJECTIVE: The major histocompatibility antigen (MHC) associations of OAD post‐allogeneic bone marrow transplantation were studied to determine whether particular subsets of patients are more susceptible to this syndrome.POPULATION: Twenty‐one of 244 consecutive patients with allogeneic transplants performed between 1980 and 1987 were identified as developing OAD after having had normal pulmonary function tests before transplant. Thirty‐nine controls were selected on the basis of normal pulmonary function tests pre‐ and post‐transplant and comparable follow‐up periods.METHODS: The study was a retrospective case‐control study. Gene frequencies of the HLA‐A and ‐B types in the patients and controls were compared and a relative risk of OAD with a given HLA allele was calculated.RESULTS: There was a significant correlation of the development of OAD with the presence of the MHC antigen, HLA‐B12 (44,45).CONCLUSIONS: These data support the idea that patients who express the HLA‐B12 (44,45) antigen are at higher risk for the development of OAD post bone marrow transplantation. However, the findings are based on retrospective analysis and accordingly should be considered tentative until followed by larger and preferably prospective studies to confirm the findings.

Autoimmune thyroid phenomena are not evidence for human lymphocyte antigen-genetic heterogeneity in insulin-dependent diabetes.

It is well established that there is genetic heterogeneity between a human lymphocyte antigen (HLA)-DR3-associated allele and an HLA-DR4-associated allele in insulin-dependent diabetes mellitus (IDDM). Equally well established are the association of DR3 with Graves' disease and other autoimmune disorders in nondiabetics and the increased prevalence of autoimmune thyroid disease in IDDM. Perhaps in large part because of these facts, it has been postulated that there are two major forms of classical IDDM--one form characterized by coexistent autoimmune disease, such as autoimmune thyroid disease which is associated with DR3, and another form not associated with additional autoimmune disorders, which is associated with DR4. Several studies have repudiated the idea of specific clinical findings in IDDM being associated exclusively with DR4. However, the DR3-thyroid association in IDDM has not been investigated carefully. Therefore, in order to study this putative association, we divided a group of diabetic children into overlapping subgroups based on thyroid enlargement, antithyroid microsomal antibodies, acquired hypothyroidism, and no evidence of thyroid disease. The distributions of HLA-DR3 and -DR4 among these subgroups did not differ from each other; nor did the distribution of the HLA alleles differ from those of randomly selected IDDM individuals. These results suggest that thyroid autoimmunity in IDDM is part of the IDDM "syndrome" and is associated with DR3 and DR4 to the same extent that IDDM without thyroid disease is associated with these two antigens. Thus, although genetic studies are consistent with the heterogeneity between DR3 and DR4 in IDDM, there is no HLA-thyroid disease association to support this heterogeneity.

Familial incidence of dermatitis herpetiformis

Dermatitis herpetiformis and gluten-sensitive enteropathy are diseases in which exposure to gluten results in an inflammatory response. Both diseases are associated with certain human lymphocyte antigen alleles, and gluten-sensitive enteropathy is well known to cluster in families. Gluten-sensitive enteropathy has also been reported in families of patients with dermatitis herpetiformis. Despite this evidence that dermatitis herpetiformis is a genetic disease, reports of the familial occurrence of dermatitis herpetiformis are rare. We have obtained family histories from 92 patients with dermatitis herpetiformis with 740 first-degree relatives. Six of these relatives have dermatitis herpetiformis. Comparison of these data with the expected prevalence of dermatitis herpetiformis shows this incidence to be highly significant (p less than 0.0001), strongly suggesting that dermatitis herpetiformis is a familial disease, presumably because of shared genetic factors but possibly because of a shared environment.