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R Tisch

Publications and source records attributed to R Tisch.

At least 37 records · Page 2Linked to original sources
PubMed1994

A predominant role of integrin alpha 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice.

To elucidate the role of cell adhesion molecules in the pathogenesis of insulin-dependent diabetes mellitus and to determine the predominant lymphocytic homing pathway(s) involved in the selective lymphocytic infiltration of pancreatic islets (insulitis), nonobese diabetic mice were treated with monoclonal antibodies specific for the L-selectin and integrin alpha 4 lymphocyte adhesion molecules. Treatment of neonatal mice with either anti-L-selectin or anti-integrin alpha 4 monoclonal antibodies for the first 4 weeks of life led to a significant and long-term protection against spontaneous occurrence of insulitis and diabetes. The same treatment failed to inhibit lymphocytic infiltration of the salivary glands (sialadenitis). This tissue-specific inhibition of inflammation may be attributed to differences between the pancreas and salivary gland in their expression of endothelial ligands for L-selectin (peripheral vascular addressin) and for integrin alpha 4 (mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1). Mucosal addressin cell adhesion molecule 1 is highly expressed by vessels within the inflamed islets but was not detected in the salivary glands. In contrast, peripheral vascular addressin- and vascular cell adhesion molecule 1-expressing vessels can be found in almost every area of inflammation within the salivary glands but are seen in only 40-50% of inflamed islets. Anti-L-selectin and anti-integrin alpha 4 treatment had no demonstrable effect on anti-beta-cell autoimmunity or on the immune responses to foreign antigens. Therapeutic treatment with anti-L-selectin after the onset of insulitis from 10 to 14 weeks of age delayed the onset but failed to prevent spontaneous insulin-dependent diabetes mellitus, whereas anti-integrin alpha 4 treatment resulted in a significant and long-lasting suppression of the disease. These data strongly suggest that integrin alpha 4 plays a prominent role in the spontaneous development of insulitis and diabetes in nonobese diabetic mice.

Animals↗
PubMed1994

Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process.

Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells.

Age Factors↗
PubMed1994

Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice.

The murine model of human insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse, develops a T cell-dependent destruction of pancreatic islets. While the target antigens are unknown, there is clearly a lack of tolerance to them. Neonatal intrathymic (i.t.) antigen injection has been successfully employed to prevent insulitis in BB rats but previous i.t. islet antigen studies in NOD mice were done on older mice. We have injected syngeneic islets into the thymus of NOD mice at birth and found that diabetes and insulitis can be completely prevented by this procedure. The effect is islet antigen-specific since other T cell responses, including autoimmune salivary infiltration, ard unaffected. Furthermore, contrary to previous studies, cyclophosphamide administration was unable to induce diabetes in treated mice which suggests that deletion or anergy might be the mechanism by which neonatal intrathymic islet injection protects from disease. However, anti-islet antigen antibodies were still present in these mice which suggests that the mechanism of disease protection may be more complex.

Animals↗
PubMed1994

Administering glutamic acid decarboxylase to NOD mice prevents diabetes.

Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy.

Animals↗
PubMed1994

Cell adhesion molecules: a selective therapeutic target for alleviation of IDDM.

Selective homing of autoreactive lymphocytes to the pancreatic islets of Langerhans is essential for triggering the cascade of molecular and cellular interactions which culminate in the specific destruction of the insulin-producing beta-cells. Based upon the sequential multistep model of lymphocyte adhesion to the endothelium, we investigated the possibility of preventing the progression of insulin-dependent diabetes mellitus (IDDM) by selectively blocking L-selectin and alpha 4-integrin homing receptors, which function at different stages of the adhesion process. Treatment of NOD mice with mAb specific for L-selectin or alpha 4-integrin resulted in a significant inhibition of lymphocytic infiltration (insulitis). Both spontaneous development and acute transfer of IDDM were completely prevented by administration of anti-alpha 4-integrin antibody and partially inhibited by anti-L-selectin antibody. The protective effect was of long duration. Interestingly, the autoimmune T cell responses to a panel of beta cell autoantigens and the lymphocytic infiltration of salivary glands (sialadenitis) appeared unaffected by anti-L-selectin or anti-alpha 4-integrin treatment. These data suggest that prevention of lymphocyte homing to the pancreatic islets may provide a selective target for prevention/treatment of IDDM in patients.

Animals↗
PubMed1994

A sequential model for peptide binding and transport by the transporters associated with antigen processing.

The TAP proteins translocate antigenic peptides into the endoplasmic reticulum. Investigation of the specificity of this process has been complicated by TAP-independent factors that influence the amount of peptide that accumulates in the ER in transport assays. We have developed an overexpression system in which binding of peptides to the TAP substrate-binding site and peptide transport by TAP can be quantified separately. Efficiency of peptide accumulation in the ER parallels affinity for the TAP substrate-binding site, but can be modified by interaction with the glycosylation system within the ER and, probably, peptide efflux. Random peptide mixtures of 9-16 aa display significantly higher affinity for the binding site than mixtures of shorter or longer peptides. Peptide binds to TAP heteromers in the absence of ATP and is released by the binding of ATP, suggesting a model for TAP function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes.

Insulin-dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, autoimmune islet damage. Our aim was to identify the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identification of the earliest beta-cell-specific autoantigen is extremely important in allowing advances in prevention and treatment of initial events in the development of inflammatory insulitis that precedes beta-cell destruction and overt diabetes. Therefore, we analyzed the proliferative responses of peripheral T-cells from young, female nonobese diabetic (NOD) mice to extracts of pancreatic beta-cell lines. We were able to demonstrate that T-cells responsive to beta-cell antigens exist in the peripheral lymphoid tissue of these mice in the absence of deliberate priming before the manifestation of histologically detectable insulitis. T-cell lines and clones isolated from the peripheral lymphatic tissues of young, unimmunized, female NOD mice were also shown to react with extracts of beta-cells. Fractionation of the beta-cell extracts showed that these T-cell clones recognized multiple beta-cell-specific autoantigens but none of the previously reported putative autoantigens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, carboxypeptidase-H, and peripherin). Thus, we can conclude that these responses are specific for novel beta-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of human islets suggesting potential shared antigenic determinants between human and mouse beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Inhibition of insulitis and prevention of diabetes in nonobese diabetic mice by blocking L-selectin and very late antigen 4 adhesion receptors.

Leukocyte adhesion to the endothelial venules in the pancreatic islets is thought to be one of the initial steps in the development of insulin-dependent diabetes mellitus. It has been suggested that leukocyte adhesion to endothelium is a sequential multistep process involving various different homing receptors. We report here that blocking different homing receptors--namely, L-selectin and very late antigen 4 (VLA-4)--which function during different stages of the adhesion process, by specific monoclonal antibodies inhibits insulitis and prevents diabetes in mice. Moreover, leukocyte attachment to the inflamed vessels within pancreatic sections could be inhibited by anti-L-selectin and anti-VLA-4 antibodies. Interestingly, anti-L-selectin or anti-VLA-4 antibody did not appear to influence the autoimmune response to a panel of pancreatic beta-cell autoantigens. These data suggest that L-selectin and VLA-4 receptors are involved in mediating leukocyte homing to the islets and that intervention of these two adhesion pathways may provide a novel approach for treatment of autoimmune diseases such as insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice.

Knowing the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic beta-cells. Several beta-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to beta-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.

Aging↗
PubMed1993

An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells.

Susceptibility to the human autoimmune disease insulin-dependent diabetes mellitus is strongly associated with particular haplotypes of the major histocompatibility complex (MHC). Similarly, in a spontaneous animal model of this disease, the nonobese diabetic (NOD) mouse, the genes of the MHC play an important role in the development of diabetes. We have produced transgenic NOD mice that express the class II MHC molecule I-Ad in addition to the endogenous I-Ag7 molecules in order to study the role of these molecules in the disease process. Although the inflammatory lesions within the islets of Langerhans in the pancreas appear similar in transgenic and nontransgenic animals, transgenic mice develop diabetes with greatly diminished frequency compared to their nontransgenic littermates (10% of transgenic females by 30 weeks of age compared to 45% of nontransgenic females). Furthermore, adoptive transfer experiments show that T cells present in the transgenic mice are able to interfere with the diabetogenic process caused by T cells from nontransgenic mice. Thus, the mechanism by which I-Ad molecules protect mice from diabetes includes selecting in the thymus and/or inducing in the periphery T cells capable of inhibiting diabetes development.

Animals↗
PubMed1992

Membrane region of surface IgM is not sufficient for transducing growth inhibitory signals in an immature B cell line WEHI-231.

The murine B lymphoma line WEHI-231 is representative of immature B cells. Like normal immature B cells, WEHI-231 is susceptible to growth arrest following cross-linking of surface IgM (sIgM). Previously, we have shown using a WEHI-231 immunoglobulin (Ig) delta-transfectant that sIgD cross-linking failed to initiate growth arrest, in contrast to sIgM. In this report, we extend our research to investigate the structural requirement of Ig mu chain for regulating growth inhibition. Recombinant, chimeric Ig molecules delta/mu m and mu/delta m consisting of exons encoding extracellular delta and mu domains and membrane regions of different isotypes were constructed and introduced into WEHI-231 cells. A similar approach was used for sIgG2b-expressing transfectants. Our findings indicate that the mu m region is not sufficient for regulation of growth inhibition in WEHI-231 cells and suggest that additional extracellular region(s) of mu chain may be required for this response.

Animals↗
PubMed1990

Parameters that govern the regulation of immunoglobulin delta heavy-chain gene expression.

The mu and delta immunoglobulin heavy-chain genes comprise a complex transcriptional unit in which a single mRNA precursor gives rise to mu- and delta-specific transcripts. During the immature B-cell stage, posttranscriptional processing events involving alternate splicing and cleavage-polyadenylation site selection give rise to mu- but not delta-encoding transcripts. In terminally differentiated B cells, delta mRNA is not synthesized because of a transcription termination event occurring upstream of the delta-gene locus. In an attempt to gain insight into the respective contributions of alternate splicing and cleavage-polyadenylation in the control of delta mRNA synthesis, we have constructed a set of plasmids in which membrane mu (mu m)-delta intergenic sequences containing the mu m poly(A) site but differing in splicing capacity were inserted in between a VH and delta gene. The mu m-delta insertion vectors were transfected into a B lymphoma line representative of an immature stage, and proximal mu m poly(A) site usage and delta mRNA synthesis were assessed. To determine unequivocally whether the mu m-delta intergenic region can regulate termination, the insertion vectors were also transfected into a B myeloma line, and transcription through the region was measured. In immature B-cell transfectants, splicing site selection was found to have a key role in determining poly(A) site utilization and concomitant delta mRNA expression. Mature delta mRNA synthesis was blocked by an upstream cleavage-polyadenylation event only when the proximal poly(A) site was associated with appropriate splicing signals. Furthermore, in vitro transcription assays revealed that the mu m-delta intergenic region is sufficient to regulate transcription termination within a 1,2430-base-pair region containing the mu m poly(A) site in myeloma transfectants. The mu m-delta insertion vectors provide an excellent model system for studying the regulatory aspects of this transcription termination event.

B-Lymphocytes↗
PubMed1988

Functional differences between immunoglobulins M and D expressed on the surface of an immature B-cell line.

Crosslinked IgM molecules expressed on the surface of immature B cells mediate responses that inhibit further development, in contrast to the activational and proliferative events that follow crosslinking of the mu heavy chain in mature B cells. Concomitant with this change in IgM signaling capacity is the appearance of surface IgD, which has been proposed to modulate the response elicited by the mu heavy chain. In an attempt to gain insight into the mechanism(s) by which surface IgM is able to generate such disparate responses, delta heavy chain gene transfectants of the murine B-cell lymphoma line WEHI-231 were established. WEHI-231 cells resemble phenotypically immature B cells, in addition to being highly susceptible to the growth-inhibitory effect of surface IgM cross-linking. Endogenous mu and exogenous delta heavy chains expressed on the surface of the transfectants were compared for their role in cell proliferation and on gene expression. Our results indicate that the growth-inhibitory response is associated only with the mu heavy chain and that surface IgD does not mediate such a response. Furthermore, in contrast to IgM, IgD molecules appear to have an inductive effect on the expression of Myc and the endogenous mu and exogenous delta Ig heavy chain genes but not on the expression of the housekeeping gene encoding beta 2-microglobulin. These findings suggest that IgM and IgD are functionally distinct when expressed on the surface of an immature B cell.

Animals↗