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T J Goldschmidt

Publications and source records attributed to T J Goldschmidt.

At least 19 recordsLinked to original sources
PubMed1998

Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis.

Immunization of mice with type II collagen (CII) leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis. T cell recognition of CII is believed to be a critical step in CIA development. We have analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q and DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However, posttranslational modifications (hydroxylation and variable O-linked glycosylation) of the lysine at position 264 generated five T cell determinants that were specifically recognized by different T cell hybridoma subsets. TCR sequencing indicated that each of the five T cell epitopes selected its own TCR repertoire. The physiological relevance of this observation was shown by in vivo antibody-driven depletion of TCR Valpha2-positive T cells, which resulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylated epitope. Most hybridomas (20/29) specifically recognized CII(256-270) glycosylated with a monosaccharide (beta-D-galactopyranose). We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire.

Amino Acid Sequence↗
PubMed1996

Dextran sulfate sodium (DSS) induced experimental colitis in immunodeficient mice: effects in CD4(+) -cell depleted, athymic and NK-cell depleted SCID mice.

Administration of dextran sulfate to mice, given in the drinking water results in acute or subacute colonic inflammation, depending on the administration protocol. This colonic inflammation exhibits ulceration, healing and repair, and a therapeutic response that makes it valuable for the study of mechanisms that could act in the pathogenesis of human ulcerative colitis, a disease thought to have an immunologically dependent pathogenesis. To investigate if immunological mechanisms were involved in the induction of colonic inflammation in this model, mice with different degrees of immunodeficiency were used. It was shown that dextran sulfate induced colitis could be induced in Balb/c mice depleted of CD4(+) helper T cells by treatment with monoclonal antibodies preceded by adult thymectomy. The depletion of CD4(+) was verified by flow cytometric analysis. Furthermore, the colonic inflammation could equally be induced in athymic CD-1 nu/nu mice lacking thymus-derived T cells, in T and B-cell deficient SCID mice, and also in SCID mice depleted of NK cells by treatment with anti-asialo GM1 antibodies. The NK-cell depletion was verified by measuring spleen NK-cell activity. The resulting colonic inflammation in all these types of deficient mice was qualitatively comparable, as shown by clinical and histological appearance. These results indicate that the presence of functional T, B and NK cells is not crucial for the induction of dextran sulfate colitis in mice.

Administration, Oral↗
PubMed1994

Therapeutic effects of monoclonal antibodies to alpha beta TCR but not to CD4 on collagen-induced arthritis in the rat.

The role which T cells play in the pathogenesis of the collagen-induced arthritis (CIA) model is not yet fully understood. Although CIA is most likely dependent on the activity of class II-restricted CD4+ T cells, only prophylactic but not therapeutic anti-CD4 treatments have been successful. The lack of therapeutically effective anti-T cell monoclonal antibody treatments has questioned the importance of T cells in ongoing CIA. However, recently we found that ongoing CIA in DA rats induced with homologous CII can be suppressed by injections with an anti-alpha beta TCR antibody. Having a CIA model where ongoing disease was clearly dependent on T cells, we addressed in the present work whether also an anti-CD4 treatment could suppress ongoing arthritis in this model. Although no CD4hi lymph node cells were seen after an anti-CD4 injection, the arthritis was suppressed only after treatment at immunization but not after treatment just before onset of disease. In comparison, the anti-TCR treatment at the time of onset was clearly suppressive even though a large fraction of the T cells was not depleted. This indicates that the different outcome of the anti-TCR and anti-CD4 treatment was not due to a different capacity to deplete T cells in vivo.

Animals↗
PubMed1992

Homologous collagen-induced arthritis in rats and mice are associated with structurally different major histocompatibility complex DQ-like molecules.

Collagen-induced arthritis (CIA) in rats, induced with homologous type II collagen (CII), is a genetically more restricted disease and has better resemblance to rheumatoid arthritis by its chronic disease course, than CIA induced with heterologous CII. The DA strain is highly susceptible to CIA induced with homologous CII, while the Lewis strain is resistant. (DAxLew)F1 is susceptible and backcrossing to Lewis reveals a close, but not complete, association of both arthritis and CII responsiveness to the RT1a haplotype. Analyses of congenic strains on DA and Lewis backgrounds suggest that expression of a major histocompatibility complex class II Ba molecule, encoded from the RT1Ba locus, is associated with arthritis susceptibility and CII responsiveness. The second exons coding for the first domains of the alpha and beta chains of both the RT1a and RT1l haplotypes were sequenced and the deduced amino acid sequences compared with the corresponding molecule associated with susceptibility to CIA in the mouse (H-2 Aq). The sequences of the respective alleles revealed no obvious structural homology explaining the extensive similarities in the development of chronic autoimmune arthritis. Instead, this finding implies that different trimolecular constituents (i.e. class II, T cell receptor, and CII peptides) may yield an antigen presentation event that is able to trigger a similar autoaggressiveness in the two rodent species.

Amino Acid Sequence↗
PubMed1992

Activated type II collagen reactive T cells are not eliminated by in vivo anti-CD4 treatment. Implications for therapeutic approaches on autoimmune arthritis.

Activation of CD4+ T cells plays an important role in type II collagen (CII) induced arthritis (CIA). The CD4+ T cell dependency is demonstrated by anti-CD4 antibody treatment which suppresses CIA in mice if injected before CII immunization. The same anti-CD4 treatment at a later stage does not suppress CIA, despite extensive elimination of peripheral CD4+ T cells. A possible explanation for this discrepancy is that activated T cells might not be as easily influenced by the anti-CD4 antibodies as resting T cells. To address this question, the proliferative capacity of CII reactive CD4+ lymph node (LN) T cells, in mice treated with anti-CD4 antibodies before or after the CII immunization, was analyzed. In mice treated before immunization the capacity of LN cells to proliferate in vitro was markedly suppressed while in mice receiving anti-CD4 treatment after immunization it was retained. Flow cytometric analysis revealed that the anti-CD4 treatment before and after immunization reduced the number of CD4+ LN T cells to the same level. The small population of CD4+ LN cells which were left after anti-CD4 treatment of naive mice all expressed CD44, a marker for previously activated T cells in mice. We propose that activation render CII reactive T cells more resistant to anti-CD4 treatment than virgin T cells are and suggest that the lack of therapeutic effect of late anti-CD4 treatment in CIA does not necessarily implicate that CD4+ T cells are unimportant in that stage of the disease.

Animals↗
PubMed1992

Arthritis induced in rats with adjuvant oil is a genetically restricted, alpha beta T-cell dependent autoimmune disease.

Adjuvant arthritis in rats is usually induced by injection of mycobacterium tubercle cell walls suspended in various adjuvant oils such as Freund's incomplete adjuvant (FIA) or pristane. We have recently shown that injection of adjuvant oils without inclusion of mycobacterium tubercle cell walls triggers arthritis [oil adjuvant-induced arthritis (OIA)] in the DA rat strain. The OIA is a genetically restricted disease since only DA rats are susceptible while Lewis, DA-fostered Lewis and F1 (Lew x DA) rats are relatively resistant. Activated alpha beta T cells infiltrate the affected joints of adjuvant oil-injected DA rats and treatment with monoclonal antibodies to the alpha beta T-cell receptor abrogates development of arthritis. These findings show that alpha beta T-cell activation is a critical event in the development of OIA.

Animals↗
PubMed1991

Anti-T cell receptor antibody treatment of rats with established autologous collagen-induced arthritis: suppression of arthritis without reduction of anti-type II collagen autoantibody levels.

Activation of T cells is critical for the development of type II collagen (CII)-induced arthritis (CIA). However, the relative importance of T cells in their delivery of help to B cells, promoting autoantibody formation or acting as inflammatory initiating cells, is unclear. The effect of a monoclonal antibody directed to the alpha/beta T cell receptor (TcR) on the development of autologous CIA was studied. Two weeks after immunization with autologous CII the onset of severe arthritis occurred, followed by a chronic arthritis activity in the peripheral joints. Anti-TcR treatment before immunization suppressed the incidence of arthritis and the autoantibody response to CII. Treatment given immediately before the expected onset delayed the appearance of arthritis. Treatment given to already arthritic rats reduced the severity. In the latter two groups the serum levels of anti-CII autoantibodies were not affected. The duration of the ameliorating effect was limited and with the return of arthritis a concomitant antibody response towards the injected mouse anti-TcR antibody was observed. These results show that the role of T cells in both the induction and perpetuation of CIA is essential and not limited to the triggering of production of pathogenic anti-CII autoantibodies.

Animals↗
PubMed1991

Host defense against cholera toxin is strongly CD4+ T cell dependent.

This study investigates the role of CD4+ T cells in host defense against cholera enterotoxin-induced diarrhea. Antitoxin immunoglobulin A formation and gut protection against cholera toxin (CT) following oral immunizations with CT were evaluated in normal mice and mice that had been depleted of CD4+ T cells by in vivo treatment with specific anti-CD4 monoclonal antibodies. Flow cytometer analysis demonstrated that anti-CD4 monoclonal antibody effectively eliminated CD4+ T cells in the spleen, mesenteric lymph nodes, and Peyer's patches. In contrast, lamina propria lymphocytes demonstrated only some decrease in CD4+ T-cell numbers following antibody treatment. However, CD4 expression of individual lamina propria lymphocytes was strongly down-regulated. Depletion of CD4+ T cells performed prior to oral immunization with CT completely inhibited the ability to respond to CT. No antitoxin production, as detected at the single-cell level by the ELISPOT technique, was found in the spleen, mesenteric lymph nodes, or Peyer's patches, nor did we observe serum antitoxin responses in these mice. Control mice demonstrated strong antitoxin responses in all locations following oral immunization with CT. Anti-CD4 antibody treatment also effectively inhibited the antitoxin immunoglobulin A response in the lamina propria to CT as well as blocked the ability to develop gut protection against CT challenge of ligated intestinal loops after oral CT immunization. Thus, in vivo CD4+ T-cell depletion rendered these mice unable to develop protective immunity in the gut following oral immunization with CT. Moreover, CD4+ T-cell depletion effectively inhibited the antitoxin immune response in the gut lamina propria, mesenteric lymph nodes, Peyer's patches, and spleen when performed prior to both priming and booster immunizations with CT. This study clearly demonstrates the requirement of functional CD4+ T cells in the gut immune system for the development of host defense against CT-induced disease. Our data also reinforce the concept of a strong association between gut protection against CT and local production of neutralizing immunoglobulin A antitoxin.

Animals↗
PubMed1991

T-cell receptor V beta haplotype and complement component C5 play no significant role for the resistance to collagen-induced arthritis in the SWR mouse.

The importance of T-cell receptor (TcR) V beta gene haplotype and complement component C5 deficiency for the resistance to collagen-induced arthritis (CIA) in the SWR mouse was studied. Firstly, the immune responses against heterologous and autologous type II collagen (CII) were compared between SWR mice and arthritis-susceptible and major histocompatibility complex (MHC)-identical DBA/1 mice. Secondly, F1 and F2 crosses were made between the two strains and studied for arthritis development, V beta gene usage and C5 presence. After immunization with heterologous rat CII, both strains reacted with a strong autoantibody response. Immunization with mouse CII, on the other hand, gave a much lower response in both strains, with DBA/1 mice having the strongest response. A collection of B-cell hybridomas was created from the draining lymph nodes of SWR mice 9 days after immunization with rat CII. This hybridoma collection showed similarity to previous data from the DBA/1 mouse, by its high frequency of B cells producing IgG specific for CII and with a high degree of cross-reactivity with autologous mouse CII. After immunization with heterologous CII, both T cells specific for heterologous CII as well as T cells cross-reacting with autologous CII could be demonstrated. F1 crosses between SWR and DBA/1 were relatively resistant to CIA (8%), while in the F2 generation 72% of the mice developed arthritis. No correlation between V beta haplotype or C5 and development of arthritis in the F2 mice was found. It is concluded that the resistance to CIA in the SWR mouse is not related to either V beta haplotype or C5 deficiency. Instead we postulate the involvement of two or more genes which are important for the induction and maintenance of tolerance to own CII.

Animals↗
PubMed1990

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters intrathymic T-cell development in mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was administered to 2-4-week-old mice (5, 25, and 50 micrograms/kg body wt.) and to in vitro cultures (10(-9) M) of fetal thymi. By monitoring thymocyte populations with respect to the differentiation antigens CD4 and CD8, it was found that the cell number in all thymocyte populations except for CD8+ decreased significantly compared with controls. In vivo the most marked decrease occurred among double negative (DN) and double positive (DP) cells, whereas in vitro, the DP cells were most severely affected. The cell number had already decreased to some extent by day 1 after a dose of 50 micrograms/kg body wt. of TCDD, although a severe reduction did not become apparent until day 4. There was a clear dose/response relationship between 5 and 50 micrograms/kg body wt. Autoradiography and liquid scintillation counting studies showed that incorporation of [3H]thymidine in the thymus had already decreased 24 h after TCDD treatment, with the decrease being even more pronounced at 48 h. By 96 h, the rate of cell proliferation had returned to approximately normal values. The results show that TCDD has a long-lasting effect on thymocyte abundance together with a transient effect on cell proliferation. This indicates that in addition to the initial effects of TCDD on cell proliferation, it may also more permanently disturb the normal process of elimination by means of selection.

Aging↗
PubMed1990

Amelioration of intrathymic T cell development and peripheral T cell reactivities in autoimmune mice undergoing therapy with a novel immunomodulator.

MRL lpr/lpr mice develop a generalized autoimmune disease associated with a massive accumulation in the peripheral lymphoid organs of abnormal, phenotypically immature T cells. Both the lymphoadenopathy and the autoimmunity are thymus-dependent and likely to arise from an aberrant pathway of intrathymic differentiation. We here present the marked beneficial effects acquired in MRL lpr/lpr mice after in vivo administration of a novel immunomodulator called linomide. The highly altered pattern of thymic subpopulations in MRL lpr/lpr mice is normalized after linomide-treatment. Concomitantly, the peripheral T cell compartment, which in MRL lpr/lpr is highly deficient in producing and responding to IL-2, gains substantial functional reactivities. We propose that linomide acts by correcting the abnormal T cell development in autoimmune MRL lpr/lpr mice. This new immunomodulator may be a useful tool for providing insight into both the pathogenesis of autoimmune disorders and intrathymic differentiation.

Adjuvants, Immunologic↗
PubMed1990

In vivo elimination of T cells expressing specific T-cell receptor V beta chains in mice susceptible to collagen-induced arthritis.

Type II collagen-induced arthritis (CIA) is believed to be dependent on T cells expressing a limited number of V beta chains. Two different methods were used to selectively eliminate T cells expressing a certain T-cell receptor (TcR) V beta chain in mouse strains susceptible to CIA. In vivo treatment with monoclonal anti-V beta 6 or anti-V beta 8.1,2 antibodies did not alter CIA, despite a reduction of the major part of the V beta 6+ or V beta 8.1,2+ lymph node cells (LNC), as measured by flow cytometric (FACS) analyses. The reduction was not due to complete elimination of V beta 6+ or V beta 8.1,2+ cells, since part of the V beta 6 and V beta 8.1,2 expressing cells returned later, even in mice that had been thymectomized first to prevent maturation of new T cells. In contrast, treatment with antibodies against CD4 efficiently abrogated development of CIA. In the (CBA x DBA/1J)F1 and the (BALB/c x DBA/1J)F1 mice, where M1s1a was combined with expression of I-E, the V beta 6+ LNC were deleted. In spite of the deletion, both F1 strains were highly susceptible to CIA.

Animals↗
PubMed1989

Oestrogen-mediated suppression of collagen-induced arthritis in rats. Studies on the role of the thymus and of peripheral CD8+ T lymphocytes.

Administration of oestrogen to castrated female rats has previously been shown to exert a suppressive effect both on the development of collagen-induced arthritis (CIA) and on the delayed-type hypersensitivity (DTH) reaction to collagen II (CII). The present study is concerned with the mechanisms responsible for this suppression, particularly as to the role of the thymus and the CD8+ T lymphocytes; both the thymic epithelial cells and the CD8+ T cells have earlier been implicated as responsible for oestrogen-mediated immunomodulation on the basis of their expression of oestrogen receptors. Adult thymectomy alone did not affect either the incidence or severity of arthritis. Furthermore, adult thymectomy did not change the observed suppressive effects of oestrogen treatment on arthritis development or auto-anti-CII T-cell immunity. Elimination of CD8+ T cells was subsequently achieved in groups of thymectomized rats by utilizing the fact that efficient depletion of CD8+ T cells occurs after in vivo treatment with OX8 monoclonal antibodies; depletion of peripheral CD8+ T cells failed to influence the suppressive effect of oestrogen on CIA and on the in vitro proliferative response of lymph-node cells to CII. Depletion of CD8+ T cells did, however, in itself reduce the incidence of CIA in non-oestrogen-treated and thymectomized rats. We conclude that oestrogen may exert its suppressive effect on development of CIA and on T-cell responsiveness via mechanisms independent of both the thymus and the CD8+ T-cell subpopulation, but that CD8+ T cells are nevertheless involved in the regulation and/or effectuation of the immune reactions responsible for development of collagen arthritis in rats.

Animals↗
PubMed1989

Collagen induced arthritis as an experimental model for rheumatoid arthritis. Immunogenetics, pathogenesis and autoimmunity.

The type II collagen (CII) induced arthritis animal model (CIA) provides opportunities to study the nature of autoimmune reactions leading to arthritis and may be used as a model for rheumatoid arthritis (RA). Thus, in similarity with RA, the CIA model, when induced with autologous CII, shows a chronic and progressive disease course. The susceptibility to both RA and CIA are correlated to the expression of certain MHC class II allotype genes. In both diseases are autoantibodies to CII and rheumatoid factors produced. Immunohistopathology of affected joints show in both diseases a dominance of activated macrophages/fibroblasts with a significant infiltration of activated T cells and an infiltration of granulocytes. We do here suggest that both RA and CIA are dependent on a synergy between delayed type hypersensitivity and immune complex mediated inflammatory mechanisms and that CIA provides opportunities for studies of immunospecific reactions leading to arthritis.

Animals↗
PubMed1988

Depletion of murine T cells by in vivo monoclonal antibody treatment is enhanced by adding an autologous anti-rat kappa chain antibody.

In vivo treatment with monoclonal antibodies can be used for elimination of various T lymphocyte subsets from peripheral lymphoid organs and blood and thereby be used both to analyze the role of different T cells in immunoregulation and for the treatment of experimental immunological diseases. However, one problem with this approach has been that not all monoclonal antibodies given in vivo eliminate their target cells. We now show in the murine system that the normally inefficiently depleting H129.19 (anti-CD4) and 53.6.7 (anti-CD8) antibodies can be used for efficient depletion of their respective target cells when combined with injection of a secondary mouse anti-rat kappa (MAR18.5) antibody. The efficacy of the depletion protocols was ascertained by double staining techniques and cytofluorometric analysis. It is suggested that the presently used sandwich method applying a homologous secondary monoclonal antibody may provide an alternative to class switching or other manipulations of primary antibodies in increasing the efficacy of in vivo antibody treatment.

Animals↗
PubMed1988

Secondary mania from cerebral embolization with nonfocal neurologic findings.

We have reported a unique example of an organic affective syndrome in a patient who had focal brain lesions, but whose initial neurologic examination was nonfocal. In retrospect, the only clue to an organic disorder was hyperreflexia in this patient with a history of alcohol abuse and clinical signs of a distal sensory neuropathy. This case emphasizes the importance of pursuing a neurologic work-up (including CT scan) in older patients with sudden mood changes, even in the absence of focal neurologic findings.

Adult↗