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J F Bach

Publications and source records attributed to J F Bach.

At least 163 records · Page 9Linked to original sources
PubMed1994

The kidney in cyclosporin A-treated diabetic patients: a long-term clinicopathological study.

This was an analysis of the renal investigations performed in 248 cyclosporin A (CyA)-treated patients who had recent-onset type I insulin-dependent diabetes mellitus (IDDM) to assess the clinicopathological relationships, risk factors and predictive indices of CyA nephrotoxicity, and renal function observed with different CyA treatment regimens. There were four different protocols, using initial CyA dosages ranging from 7.5 to 10 mg/kg/day, with dose modification according to serum creatinine concentration, which was measured regularly in some patients for up to 9 years after starting treatment. Kidney biopsies were obtained from 125 patients (74 adults and 51 children) who had received only CyA for an average duration of 13 months before biopsy and had no other sources of renal injury at this stage of IDDM. Of these patients, 58% showed normal or minimal changes on biopsy, 26% showed slight abnormalities, and 16% showed medium-grade (grade III nephropathy) abnormalities. Lesion severity was related to the degree of interstitial fibrosis and tubular atrophy which, in turn, was related to the use of high maximum CyA dosages. Patients' age, and excessive CyA dose and blood trough levels were the main risk factors, and serum creatinine increase was the best predictive factor of CyA-induced nephropathy. However, CyA-induced renal dysfunction was essentially reversible on dosage reduction, and morphological changes were not followed by progressive renal insufficiency when CyA doses were low and adjusted according to serum creatinine levels. We conclude that, at present, it is recommended that low-dose CyA in combination with other non-nephrotoxic immunosuppressive strategies be used in patients with IDDM.

Adult↗
PubMed1993

Retraction.

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Retraction Notice↗
PubMed1993

Strategies in immunotherapy of insulin-dependent diabetes mellitus.

Complete and definitive prevention of diabetes obtained in animal models by using a number of diversified maneuvers has elicited major hope for immunoprevention of the disease in man. Therapeutic trials of immunosuppressive drugs in human IDDM have opened the way towards prevention or cure of the disease. Difficulties encountered, including requirement for chronic immunosuppression and risk of metabolic relapses, suggest two complementary approaches: precocious intervention based on early and reliable disease prediction, and tolerance-inducing regimens, hopefully using shorter and innocuous therapy. Animal data suggest that this is indeed an achievable goal.

Animals↗
PubMed1993

Evidence for a preferential V beta usage by the T cells which adoptively transfer diabetes in NOD mice.

Non-obese diabetic (NOD) mice become spontaneously diabetic as a result of a genetically programmed autoimmune process mediated by autoreactive T lymphocytes and directed against beta cell antigen(s). Studies dealing with T cell receptor (TcR) variable (V) gene usage by such autoreactive T lymphocytes have given contrasted results. Various reasons may explain these discrepancies: the multiplicity of antigenic epitopes putatively recognized by T cells, the ambiguity between specifically committed T cells and passenger lymphocytes homing randomly to the pancreas, the necessarily limited size of the T cell clone panels which have been analyzed for TcR rearrangements and, last but not least, the flexibility of T cell repertoires. To circumvent some of these difficulties, we have decided to concentrate upon the T cell population present in diseased animals and capable of transferring diabetes into young naive NOD recipients. This population, composed of CD4+ and CD8+ T cells, is presumably committed against the relevant beta cell antigens and is the most likely to reveal a bias in V gene usage if such a bias does indeed exist. To find out whether certain V beta genes are more frequently used than others by such pathogenic T cells, T lymphocytes from diabetic donors have been depleted in vitro of defined V beta subsets before being reinoculated into permissive recipients. Out of four V beta families probed under such conditions, three (V beta 8, V beta 5 and V beta 11) are neutral. Their absence neither increases nor reduces the final incidence of successful transfers, indicating that these gene segments are not preferentially used. In contrast, the depletion of V beta 6-positive T cells results in a severe reduction of transfers, suggesting that V beta 6 gene is used with a relatively high frequency by diabetogenic CD4+ and/or CD8+ T cells. To define more precisely which subset uses V beta 6 gene preferentially, we have performed mixing experiments with deleted and intact subsets. The results, based on disease transfer and insulitis severity, indicate that the V beta 6 bias affects predominantly the CD4+ subset. Thus, at variance with several studies concluding that V gene usage in NOD mice is heterogeneous, our present data suggest that disease transferring T cells use a relatively restricted set of V beta genes.

Animals↗
PubMed1993

Protection from insulin-dependent diabetes mellitus is linked to a peptide transporter gene.

HLA class II association with insulin-dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult-onset and 51 childhood-onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for the TAP2*0201 allele [relative risk (RR) = 0.3, corrected probability (pc) < 0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR = 3.4, pc < 0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR = 0.06, pc < 0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB1*0302 haplotypes predisposing effect (RR = 1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed by chi 2 analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies (p < 0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to beta cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM prediction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Establishment of T-cell lines from infiltrated NOD islets by stimulation of specific T-cell receptor V beta segments.

The aims of this study were firstly to establish permanent T-cell lines from infiltrated NOD islets, by repeated stimulation of the antigen T-cell receptor with anti-V beta monoclonal antibodies (mAb) and, secondly, to characterize some of their cytotoxic and pathogenic properties. The use of anti-V beta antibodies was aimed at driving the expansion of the T cells in the absence of pancreatic antigen and, at the same time, at selecting lymphocytes expressing a given V beta gene product as an element of their TCR. Twelve lines were established as long-term cultures by regular stimulation with plastic-bound anti-V beta 6 or anti-V beta 8 mAb. The eight lines cultured with anti-V beta 6 mAb were phenotyped as early as one month after initiation and were all V beta 6+/V beta 8-. Three were CD8+ and five CD4+. Of the four lines established with anti-V beta 8 mAb, three were V beta 8+/V beta 6- and one (FD) was unexpectedly phenotyped as V beta 6+/V beta 8-. Clones derived from the FD line confirmed the expression of V beta 6. The cell-mediated cytolytic properties of the 12 lines were evaluated in two independent assays: an antibody-redirected assay to measure the lytic potential irrespective of antigen specificity and a direct cytolytic assay on YAC cells for assessing NK-like activity. The results indicate that practically all the lines (11 out of 12), irrespective of their CD4/CD8 phenotype or V beta expression, can exert cell-mediated cytotoxicity when their TCR/CD3 complex is linked to a target cell. On the other hand, anti-YAC activity is almost exclusively confined to CD8+ cell lines. Pathogenicity was evaluated in two CD4+ T cell lines, one which showed cytolytic activity in the redirected assay but not in the YAC assay (FD) and one which was totally devoid of cytotoxic activity (AH). The two lines were injected into newborn NOD mice with or without CD8+ polyclonal T cells. The results indicate that FD, the cytotoxic line, can induce severe lesions of insulitis when coinjected with polyclonal CD8+ T cells. In contrast, AH, the non-cytotoxic line, injected under the same conditions, induces no lesions. Altogether, the present data demonstrate the feasibility of establishing permanent T-cell lines on the basis of V beta expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Cellular basis of T-cell autoreactivity in autoimmune diseases.

There is no doubt that T cells play a key role in the pathogenesis of autoimmune diseases (AD) both as effector and regulatory cells. Despite spectacular progress in the understanding of natural tolerance to self, owing particularly to transgenic technology, important questions remain open regarding the pathogenesis of AD, the conditions favoring the transition from benign or 'physiological' autoimmunity to deleterious autoimmunity, and the precise effector mechanisms. This review on the cellular basis of T-cell-mediated AD begins with an enumeration of the main arguments in favor of direct T-cell involvement, special emphasis being given to two animal models which have been most extensively investigated: experimental allergic encephalomyelitis, and the nonobese diabetic mouse. The question as to whether pathogenic T cells use a restricted repertoire of V beta genes is examined in the context of these two models. From here we proceed to an evaluation of the mechanisms of onset of AD, discussing both extrinsic and intrinsic factors responsible for the breakdown in T-cell tolerance and reviewing the arguments in favor of suppressor T cells being actively involved in the prevention of autoimmunity. The last two sections are devoted to the effector mechanisms responsible for tissue injury in organ-specific AD and to T-cell-directed therapeutic interventions, respectively. We discuss the two main pathogenic hypotheses based on direct intervention of cytotoxic T cells or indirect involvement of inflammatory cytokines and macrophages, and evaluate the importance of ecotaxis in leading autoreactive T cells to the site of injury. We conclude on a brief and nonexhaustive list of strategies aimed at selectively neutralizing potentially harmful T cells.

Animals↗
PubMed1993

Evidence for antigen driven selection in two monoclonal auto-antibodies derived from nonobese diabetic mice.

The nonobese diabetic (NOD) mouse is a model of human type I diabetes. This diabetes is due to massive infiltration of the pancreatic beta cell of islets by autoreactive T cells (insulitis) followed by the destruction of insulin-producing cells. Circulating autoantibodies are also detected, notably against glutamic acid decarboxylase, peripherin and insulin. Two monoclonal autoantibodies directed against insulin and peripherin were obtained by fusing NOD spleen and myeloma cells. We report here the nucleotide sequence of the genes encoding for the V regions of these two antibodies. Somatic mutations were identified by comparing the light chain nucleotide sequence of one of these autoantibodies with its germline counterpart precursor established from NOD mice after PCR gene amplification. The other one displays N additions on both sides of the D region. These results strongly suggest that both autoantibodies have undergone diversification, either N additions or somatic mutations, and therefore present structural features of antibodies derived from animals immunized against exogenous antigens.

Amino Acid Sequence↗
PubMed1993

Identification by genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis.

HLA association with myasthenia gravis (MG) has been studied in a series of 114 patients using class I and class II genotyping after PCR amplification. Positive association was found with DR3, particularly in women (RR = 2.6) and in early MG onset (RR = 3.4). DRB1, DRB3, DQB1, DQA1 and B (B8 and B18) genotyping revealed that the association was predominantly with the B8 DRB1*03 DRB3*0101 DQB1*0201 DQA1*0501 ancestral haplotype. This haplotype frequency was also increased in patients with thymic hyperplasia (RR = 3.5) and was greatly reduced in patients with thymoma (RR = 0.35). Sixteen out of 48 patients carrying this 8.1 ancestral haplotype showed absence of B8 (n = 4) or of DR3 (n = 12). HLA class II genotyping further revealed the existence of two other significant associations. MG was positively associated with the DQB1*0604 allele (RR = 3.4), particularly in patients with thymoma (RR = 5.7). Furthermore, the disease was negatively associated with DR1 in females (RR = 0.32). These data suggest that MG is placed under the control of at least three distinct genes: (1) a class II predisposing gene in the 8.1 ancestral haplotype; (2) a thymoma-associated class II allele on the DQB1*0604 haplotype; and (3) a protective allele DR1.

Age Factors↗
PubMed1993

Immunosuppressive therapy of autoimmune diseases.

Ciclosporin and cyclophosphamide show a remarkable efficacy in most autoimmune diseases. However, their effect is dependent on continuous drug administration with risks of drug toxicity and over immunosuppression. Results recently obtained in animal models, discussed here by Jean François Bach particularly with anti-CD3 and anti-CD4 monoclonal antibodies, indicate that reestablishment of tolerance to self antigens is a feasible goal.

Animals↗
PubMed1993

Immunosuppressive therapy of autoimmune diseases.

Cyclosporin A, corticosteroids and cyclophosphamide show a remarkable efficacy in a large number of autoimmune diseases. However, their effect is dependent on continuous drug administration with potential risks of drug toxicity and over immunosuppression. Results recently obtained in animal models, particularly with anti-CD3 and anti-CD4 monoclonal antibodies, indicate that reestablishment of tolerance to self antigens is a feasible goal.

Animals↗