Herpes simplex virus type 1 (HSV-1) specific T-cell generation from HLA-A1- and HLA-A2-positive donors for adoptive immunotherapy.

BACKGROUND AIMS: Herpes simplex virus (HSV) reactivation and infection is common in patients undergoing hematopoietic stem cell transplant (HSCT) and requires routine antiviral prophylaxis. Drug-resistant strains are increasingly common, and effective alternative therapy is currently unavailable. We generated and characterized HSV-1-specific T cells for use in adoptive cellular immunotherapy following allogeneic stem cell transplantation. METHODS: Peripheral blood mononuclear cells from HLA-A1 and HLA-A2 HSV-seropositive hereditary hemochromatosis donors were used as the antigen source. Three HLA-A1 and four HLA-A2 specific epitopes were used for stimulation of T cells. Cells were stimulated with antigen-pulsed dendritic cells and cultured for 21 days in medium with interleukin (IL)-2. Cultured cells were phenotyped and tested for cytokine production, proliferation and cytotoxicity. RESULTS: There was a 5.3-fold expansion in total cell numbers over 21 days of culture, with 35% of T cells being CD8 positive. Thirty-five percent, 21% and 5% of CD8 cells secreted interferon-γ, tumor necrosis factor-α and IL-2 upon HSV antigen re-stimulation. More than 50% of antigen-specific T cells secreted multiple cytokines. Cultured T cells proliferated upon antigen re-stimulation and lysed HSV-1 peptide and virus-infected targets. CONCLUSIONS: It is feasible to generate functional HSV-1 specific T cells from the blood of HLA-A1 and HLA-A2 HSV-seropositive donors using specific peptides. The utility of these cells in preventing and treating HSV-1 reactivation in allogeneic HSCT will need to be tested clinically.

Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives.

OBJECTIVE: Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families. METHODS: To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS). RESULTS: Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive. CONCLUSIONS: Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

Sensorineural hearing loss associated with birdshot retinochoroidopathy.

We treated a patient with birdshot retinochoroidopathy, an autoimmune eye disease. An autoimmune sensorineural hearing loss developed, probably due to endolymphatic hydrops. To our knowledge, the association of these two conditions has not been recorded previously.

Alloantibodies to human platelet glycoprotein antigens (HPA) and HLA class 1 in a cross section of Nigerian antenatal women.

The prevalence of antibodies to human platelet antigens (HPA) and human leukocyte antigens (HLA) class 1 antigens among Nigerian pregnant women has not been reported in our country. This study was therefore aimed at screening the obstetric population for evidence of alloimmunization due to human platelet and HLA class 1 antigens. One hundred and forty four (144) pregnant women attending the obstetric clinic of Military Hospital, Port Harcourt, participated in the study. Their sera were tested for antibodies to HPA and HLA class 1 antigens using GTI PakPlus solid phase ELISA Kit. The total prevalence rate of antibody production was 60.5% (87 out of 144). Among the positive samples, 60 had platelet glycoprotein specific antibodies (41.7%) and 27 had HLA class 1 antibodies (18.8%). In 39.6% of the pregnant women, both platelet specific antibodies and HLA class 1 antibodies appeared. The prevalence of platelet specific glycoprotein antibodies were obtained as follows: GP 11b/111a 12 (8.3%), GP 1a/11a 35 (20.8%), GP Ib/IX 18 (12.5%) and GP IV 9 (6.3%). The prevalence of each platelet antibody subgroup was obtained as follows: anti-HPA-1a,-3a,-4a (4.2%), anti-HPA-1b,-3b,-4a (4.2%), anti-HPA-30 5a and anti-GP Ib/IX (12.5% each), anti-HPA-5b (8.3%) and anti-GP IV (6.3%). A high prevalence rate of human platelet arid cytotoxic antibodies has been observed in our obstetric population. There is need to establish platelet serology laboratory for the proper antenatal and postnatal management of pregnant mothers in this region.

Soluble Human Leukocyte Antigen class I antigen and interleukin-12 in hepatectomized patients.

BACKGROUND: Interleukin-12 (IL-12) has been shown to enhance the cytotoxic activity of NK cells and CTL. IL-12 also acts as a growth factor for activated NK, T and NKT cells. The soluble HLA class I (sHLA-I) has been reported to bind a killer-cell inhibitory receptor, which is expressed on the NK cell, and its signals inhibit NK cell-mediated cytotoxicity. Effects of fresh frozen plasma (FFP) on post-operative immune status have not yet been completely examined. METHODS: Thirty consecutive patients taking a hepatectomy were enrolled. The levels of IL-12 and sHLA-I were examined by enzyme-linked immunosorbent assay. RESULTS: The rate of complication after hepatectomy in the FFP-administered patients was higher than that in patients without FFP administration (P = 0.0358). Decreased IL-12 levels after surgery in patients without FFP administration recovered to the preoperative state earlier than those in patients with FFP administration (P < 0.05). The levels of sHLA-I in the FFP-administered patients were higher than those in the patients without FFP administration (P < 0.05). CONCLUSIONS: Administration of FFP, which contains sHLA-I, affected the levels of sHLA-I after hepatectomy. Both high levels of sHLA-I and low levels of IL-12 could attenuate NK activities after hepatectomy, especially when FFP would be administered.

Human leukocyte antigen and esophageal cancer in the northwestern region of Iran.

Esophageal squamous cell carcinoma is the 6th most commonly occurring cancer worldwide. A relationship between HLA A1 and B40 and esophageal cancer was described in patients examined in China. The aim of this study was to investigate the relation of HLA class 1 and esophageal carcinoma in the northwestern region of Iran. Using specific monoclonal antibodies, different human leukocyte antigens (HLA) were quantified in 100 patients suffering esophageal carcinoma in Tabriz, a major city located in the Northwestern region of Iran. These data were compared to those of 100 healthy matched individuals as a control group from the same region. HLA B14 and A24 were increased and showed statistically significant correlation in squamous cell carcinoma. These findings may also indicate the association between genetic factors and esophageal carcinoma. Further studies are suggested for detecting correlation of HLA and esophageal carcinoma in other regions.

Human leukocyte antigen-A2.1 restricted candidate cytotoxic T lymphocyte epitopes of human papillomavirus type 16 E6 and E7 proteins identified by using the processing-defective human cell line T2.

Human papillomavirus type 16 (HPV-16) is strongly associated with cervical cancer. HPV-16 cytotoxic T lymphocyte (CTL) epitopes may be good candidates for the development of an antitumor peptide vaccine. A set of 240 overlapping peptides nine amino acids in length with an eight amino acid overlap covering the entire sequence of the two viral oncogenes E6 and E7 was synthesized and tested for its ability to bind to the most common human leukocyte antigen class I molecule HLA-A2.1. Binding was measured with the human processing defective cell line T2, which expresses high numbers of empty HLA-A2.1 molecules that are unstable at 37 degrees C. These empty molecules can be stabilized by exogenously added peptides, and the extent of stabilization, measured by cell surface HLA-A2.1-specific staining, can be taken as a measure of the relative HLA-A2.1 binding affinity. Following this analysis, several HLA-A2.1 binding peptides were pinpointed. Preliminary data suggest that at least one of the high-affinity-binding peptides identified is immunogenic even in an in vitro priming protocol, underlining the feasibility of the method described here to identify the immunogenic peptides and potential candidates for CTL peptide-based vaccines.

[Immunogenetic factors in pulmonary tuberculosis surgery]. / Immunogeneticheskie faktory vo ftiziokhirurgii.

Distribution of HLA antigens, haptoglobin phenotypes (Hp), ABO blood groups and rhesus factor was investigated in 60 patients with fibrocavernous tuberculosis and 50 patients with tuberculomas. All the patients were Russian and had a history of surgery for tuberculosis. Carriers of antigens B27, DR2 of HLA system, HP 2-2 and blood group 0 (I) were encountered more often in the group of tuberculosis patients. Antigens A1, B12, DR3 and A2 occurred among tuberculoma patients more frequently and less frequently, respectively. Among those who developed postoperative complications carriers of blood group A (II) were found significantly less frequently. Antigens HLA and Hp types were unrelated to the incidence of pleuropulmonary and infectious postoperative complications. Tuberculosis reactivation in the postoperative period and postoperative recurrences occurred more often in carriers of HLA antigen DR2.

Treatment of alloimmune neonatal neutropenia with granulocyte colony-stimulating factor.

Despite numerous attempts to increase the neutrophil count of infants with alloimmune neonatal neutropenia, no therapy has been consistently effective. We describe two infants with alloimmune neutropenia who had a rapid and prolonged increase in neutrophil number after treatment with granulocyte colony-stimulating factor (G-CSF). Patient 1 had antibody directed against the neutrophil antigen NA2. He received three daily doses of G-CSF, and within 2 days his neutrophil count increased from 0.350 x 10(9) to 3.584 x 10(9)/L (350 to 3584/mm3). Despite cessation of treatment the neutrophil count remained in the normal range. Patient 2 had antibody to the neutrophil antigen NA1, and received six daily doses of G-CSF. Within 4 days his neutrophil count increased from 0.477 x 10(9) to 4.320 x 10(9)/L (477 to 4320/mm3) and remained in the normal range for 11 days after the last dose of G-CSF. We recommend that treatment with G-CSF be considered for selected infants with alloimmune neutropenia.