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Biomedical subjects

T H Eiermann

Publications and source records attributed to T H Eiermann.

At least 19 recordsLinked to original sources
PubMed2001

The effect of IgM-enriched human Ig and rabbit antithymocyte globulin on the stimulation of mononuclear cells.

Whether IgM-enriched intravenous Ig (pentaglobin) is a useful adjunct treatment for graft versus host disease (GvHD) prophylaxis in allogeneic stem-cell transplantation is unclear. Clinical data with the use of a five-agent GvHD prevention regimen, including pentaglobin and antithymocyte globulin (ATG), are encouraging. In vitro both have been reported to modulate alloreactive T cells. We compared their inhibitory effect on the phytohemagglutinin-induced lymphocyte proliferation. ATG blocked the proliferation of lymphocytes at lower doses and much stronger than pentaglobin. The combination of both was not different from ATG alone. In pentaglobin, glucose used as stabiliser, caused the effect. Starting at a concentration of 40 mg/dL glucose, glucose alone showed a dose-dependent inhibition of phytohemaglutinin (PHA)-induced proliferation. For the in vivo application of pentaglobin, the results suggest that pentaglobin does not inhibit the proliferation of T cells.

Animals↗
PubMed2001

Jurkat cell-reactive anti-thymocyte globulin assessed ex vivo by flow cytometry persists three weeks in circulation.

Rabbit anti-thymocyte globulin (ATG-Fresenius) is a polyclonal anti-serum raised against the lymphoblastic T cell line Jurkat. It is used for in vivo depletion of host and donor T cells for allogeneic stem cell transplantation. After administration of 90 mg/kg prior to transplant, rabbit immunoglobulin G (IgG) remains present for 4-5 weeks, but it is unknown how long T cell-reactive antibodies persist. Therefore, we measured anti-Jurkat antibodies by flow cytometry. The detection limit for Jurkat-reactive antibodies was 0.1 microg/ml rabbit IgG; half-maximal labeling of Jurkat cells required 183 microg/ml rabbit ATG. The mean half-life of Jurkat-reactive antibodies in 7 patients was 4 days. Detectable levels persisted up to 3 weeks with antibody levels equivalent to 0.2-4.1 microg/ml rabbit ATG. Jurkat-reactive antibodies were eliminated two-fold faster than rabbit IgG, as assessed by enzyme-linked immunosorbent assay (ELISA). The results suggest that in patients pretreated with ATG before transplantation, residual anti T-cell antibodies may effectively modulate recovery of T cells generated after transplantation, thereby lowering the incidence of severe GVHD.

Animals↗
PubMed2000

PERB11 (MIC): a polymorphic MHC gene is expressed in skin and single nucleotide polymorphisms are associated with psoriasis.

The susceptibility genes for psoriasis remain to be identified. At least one of these must be in the major histocompatibility complex (MHC) to explain associations with alleles at human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and C4. In fact, most of these alleles are components of just two ancestral haplotypes (AHs) designated 13.1 and 57.1. Although relevant MHC gene(s) could be within a region of at least 4 Mb, most studies have favoured the area near HLA-B and -C. This region contains a large number of non-HLA genes, many of which are duplicated and polymorphic. Members of one such gene family, PERB11.1 and PERB11.2, are expressed in the skin and are encoded in the region between tumour necrosis factor and HLA-B. To investigate the relationship of PERB11.1 alleles to psoriasis, sequence based typing was performed on 97 patients classified according to age of onset and family history. The frequency of the PERB11.1*06 allele is 44% in type I psoriasis but only 7% in controls (Pc = 0.003 by Fisher's exact test, two-tailed). The major determinant of this association is a single nucleotide polymorphism (SNP) within intron 4. In normal and affected skin, expression of PERB11 is mainly in the basal layer of the epidermis including ducts and follicles. PERB11 is also present in the upper keratin layers but there is relative deficiency in the intermediate layers. These findings suggest a possible role for PERB11 and other MHC genes in the pathogenesis of psoriasis.

Base Sequence↗
PubMed1999

Monitoring anti-thymocyte globulin (ATG) in bone marrow recipients.

The present study was undertaken to acquire a rationale for clinical dose adjustment of anti-thymocyte globulin (ATG) to improve cost effectiveness and safety of graft-versus-host disease prophylaxis. The concentration of rabbit ATG in the serum of 12 patients was measured by ELISA and by the inhibitory effect on phytohaemagglutinin-induced blastogenesis. At 10 mg/ml ATG, 3H-thymidine incorporation was effectively blocked. Serial two-fold dilution of ATG showed that this effect decreased in a concentration-dependent manner and was lost at 10 ng/ml ATG. One hundred microlitres serum taken at day -1 to +22 post transplant effected significant inhibition of the phytohaemagglutinin-response with 49+/-12% c.p.m. (x +/- s.d.) on day +1 post transplant compared to 93+/-13% c.p.m. on day -1 (P<0.001, unpaired one-sided t-test). The rabbit-IgG was maximal at a concentration of 907+/-187 microl/ml at day 0. Subsequently, it decreased with time. While rabbit-IgG was detectable for a long period (e.g. 160 microg/ml at day +22 in patient MD), the effect on the phytohaemagglutinin-response of normal mononuclear cells lasted up to 4 days post transplant. We conclude that 90 mg/kg body weight ATG-Fresenius given prior to marrow transplant leads to sustained T cell immunosuppression post transplant.

Adult↗
PubMed1998

HLA and alveolar echinococcosis.

Evidence in animal intermediate hosts that susceptibility to larval infection with Echinococcus multilocularis is restricted to individual host factors prompted us to investigate the susceptibility markers in humans. Because antigens of the extracellular parasite E. multilocularis are possibly presented by MHC molecules in a restricted way, we speculated that MHC polymorphism may influence resistance of the host towards infection and course of disease. We studied HLA-A, -B, -DRB1, -DQB1 and -DPB1 polymorphism in 151 patients with alveolar echinococcosis. Patients with an observation period of more than 2 years were grouped according to the clinical follow-up into cured (no recurrence following surgery) patients and patients with regressive or progressive forms of disease during benzimidazole chemotherapy. By comparing phenotypic frequency between patients with alveolar echinococcosis and healthy controls, HLA-DRB1*11 was associated with a reduced risk for disease development (odds ratio=0.55, 95% confidence interval=0.34-0.88; P=0.01). HLA-DQB1*02 was more frequent in patients with progressive disease when compared with patients with regressive disease (54.3% vs 28.3%, P=0.02). The result suggests that HLA-DRB1*11 might confer protection against alveolar echinococcosis and that HLA-DQB1*02 may indicate a risk for progressive disease development. The findings may facilitate the search for immunodominant T-cell epitopes of E. multilocularis.

Animals↗
PubMed1998

Serological and molecular analysis of HLA class I and II alleles in Thai patients with psoriasis vulgaris.

The HLA class I and class II alleles in 67 patients with type I psoriasis vulgaris, 23 patients with type II psoriasis vulgaris and 140 healthy individuals were analyzed. The frequencies of HLA-A2, -B46, -B57 and DQB1*0303 were significantly increased in type I psoriasis compared to the controls (Pc<0.05). Molecular analysis of HLA-A2 alleles showed an increase in HLA-A*0207 and a decrease in HLA-A*0203 in type I psoriasis. HLA-DQB1*0301 was significantly decreased in type I psoriasis compared to the normal controls (Pc<0.05). No association of any alleles with type II psoriasis was observed. This data demonstrated two susceptible haplotypes: HLA-A1-B57-DRB1*0701-DQA1*0201-DQB1*0303 (AH57.1) and HLA-A2-B46-DRB1*0901-DQA1*0301-DQB1*0303 (AH46.1) for type I psoriasis in the Thai population. Besides, the haplotype AH46.1 was also associated with type II psoriasis.

Adult↗
PubMed1998

Human monoclonal antibody with T-cell-like specificity recognizes MHC class I self-peptide presented by HLA-DR1 on activated cells.

Alloreactive T cells recognize peptides presented in the binding groove of major histocompatibility complex molecules (MHCs), whereas B cells mainly recognize the MHCs independent of bound peptides. Here, we demonstrate that the human B-cell repertoire comprises B cells which can be stimulated during pregnancy to produce antibodies reacting with MHCs in a way similar to T cells. The human monoclonal antibody UL-5A1 recognizes DR1(DRA/DRB1*0101) molecules on lymphoblastoid cell lines only if they co-express HLA-A2 or if they have been loaded with HLA-A2-derived peptides. The effect of the HLA-A2 peptide 105-117 on UL-5A1 reactivity was specific, time and dose-dependent. Reactivity increased when naturally processed peptides were removed from DR1 molecules before the HLA-A2 peptide 105-117 was loaded. UL-5A1 reacted specifically with cells that had been activated. The results imply a role of activation of cells in peptide processing and/or loading.

Amino Acid Sequence↗
PubMed1997

Tumor necrosis factor-alpha gene polymorphism in psoriasis.

Psoriasis, an inflammatory autoimmune disease, is characterized by increased level and activity of the proinflammatory cytokine TNF-alpha in affected lesions. Two promoter region polymorphisms of the TNF-alpha locus--one at position -308 and the other at -238--were examined in 99 Caucasian patients (64 with type I and 35 with type II psoriasis) and in 123 controls. A highly significant difference in the distribution of the -238 polymorphism--the TNF (G,A) genotypes--was detected between the type I psoriasis patients and controls: compared to the controls, the frequency of the homozygous TNF-G genotype was decreased (55 vs. 91%; p = 0.0000000274; corrected p = 0.0000001644; odds ratio = 0.12), whereas that of TNF-G,A heterozygotes was increased (41 vs. 8%; p = 0.000000264; corrected p = 0.000001584; odds ratio = 7.73) in patients. No significant differences were observed in the distribution of the TNF-A homozygotes. These results suggest that homozygosity of the G allele is associated with a lower relative risk (resistance), whereas heterozygosity at this locus is associated with an increased risk (susceptibility) of type I psoriasis.

Humans↗
PubMed1996

Evidence for somatic mutation and affinity maturation of diabetes associated human autoantibodies to glutamate decarboxylase.

The processes that lead to the production of islet cell autoantibodies in insulin-dependent (type 1) diabetes mellitus (IDDM) are largely unknown. Humoral autoimmunity may be the result of an antigen-independent polyclonal B cell activation, or a consequence of an antigen driven B cell activation and selection for the antigen. We have analysed the gene elements encoding the immunoglobulin variable regions of seven human monoclonal islet cell antibodies (MICA) 1-7 directed to the major islet autoantigen glutamate decarboxylase (GAD65). These autoantibodies were derived from two patients with newly diagnosed IDDM. The variable gene regions of the MICA revealed different sequences, and no relation between V gene usage and shared epitope recognition of the MICA was evident. An elevated usage of VH 1, VH 4 and Vlambda 2 gene segments was observed. The underrepresentation of VH 3 family members in the MICA discriminated them from most autoantibodies. The high relative avidities for GAD65 of MICA 1, 3, 4 and 6 and their high, nonrandom ratio of replacement versus silent mutations in the antigen binding regions indicated that the humoral response to GAD65 is driven by the antigen. MICA 2, 5 and 7 showed as well an excess of replacement mutations in the antigen binding regions, but revealed lower relative avidities for their antigen. Since these clones accumulated many somatic mutations in their variable gene regions, they may be characteristic for later stages of the autoimmune disease. The results suggest that, in humans, an antigen driven B cell activation and affinity maturation process may contribute to the production of GAD65-autoantibodies found in patients with IDDM.

Antibodies, Monoclonal↗
PubMed1996

Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303: a population- and family-based study.

To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.

Base Sequence↗
PubMed1995

Immunoglobulin variable gene analysis of human autoantibodies reveals antigen-driven immune response to glutamate decarboxylase in type 1 diabetes mellitus.

Insulin-dependent (type 1) diabetes mellitus is an organ-specific autoimmune disease frequently associated with an islet-specific humoral autoimmune response. The role of islet cell autoantibodies in the disease process is unclear; in particular, it is not known whether they are a non-specific side effect of islet cell destruction or play a role in the autoimmune network leading to type 1 diabetes. Here we report the immunoglobulin gene usage and somatic mutation rates of a panel of seven human monoclonal islet cell autoantibodies (MICA 1-7) directed towards the major islet cell autoantigen glutamate decarboxylase (GAD). These autoantibodies were produced from cells from two patients with newly diagnosed type 1 diabetes. VH1, VH4 and V lambda 2 gene segments were frequently used in the MICA, but no correlation between V gene usage and epitope recognition was found. The nonrandom ratio of replacement versus silent mutations in the variable gene region, an accumulation of replacement mutations in the complementarity determining regions, which confer antigen binding, and the high relative avidity for GAD observed for MICA 1, 3, 4, and 6, suggested that the immune response to GAD is driven by the antigen. In contrast, MICA 2, 5, and 7, revealing a lower affinity for antigen, have accumulated a large number of silent mutations. These latter antibodies may, therefore, be characteristic for later stages of the chronic autoimmune disease. Our results argue in favor of an antigen-driven autoantibody response to islets in human type 1 diabetes. They suggest that GAD is an important target of autoimmunity associated with type 1 diabetes.

Amino Acid Sequence↗
PubMed1995

Characterization of two human IgM monoclonal antibodies reactive with HLA-B27.

We describe here the generation and characterization of two human monoclonal IgM antibodies (UL-4F11 and UL-F6) reactive with HLA-B27. The monoclonal antibody (mAb) UL-4F11 is cytotoxic for peripheral mononuclear cells and, therefore, useful as typing reagent for HLA-B27 and HLA-B38. Protein chemistry showed that the mAb UL-4F11 precipitates HLA-B27 molecules. Epitope mapping analysis suggests that the amino acids 45, 67, 82 and 83 (alpha-1 domain) of the HLA-B27 sequence are necessary for mAb UL-4F11 reactivity. The mAb UL-F6 is suitable for complement dependent lysis of lymphoblastoid cell lines and stimulated peripheral blood mononuclear cells with HLA-B27 (B*2701, B*2702, B*2703, B*2705, B*2707), B13, B40 (60,61), B47 and B48 specificities. Its reactivity indicates that the amino acid valine in position 152 and glutamic acid in position 163 of the alpha-2 domain are crucial for the binding epitope.

Amino Acid Sequence↗
PubMed1995

HLA and bone marrow transplantation.

Bone marrow transplantation between HLA-identical siblings is an established therapeutic strategy in leukemia and a variety of lympho-hematopoietic disorders. In recent years unrelated donors were increasingly used for patients lacking a family donor. Here we report on current progress in HLA class II typing by molecular methods which have influenced donor search and improved matching.

Bone Marrow Transplantation↗