In-vivo anti-CD3 treatment of autoimmune patients.
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Antibodies, Monoclonal↗
Biomedical subjects
J F Bach
Publications and source records attributed to J F Bach.
Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma [corrected].
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Antibodies, Monoclonal↗
T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.
The nonobese diabetic (NOD) mouse has recently been introduced as a model for insulin-dependent diabetes mellitus. The role of regulatory T cells in the development of antipancreatic autoimmunity in this model remains unclear. To evaluate the presence of suppressive phenomena, we used disease transfer by spleen cells from diabetic NOD mice into preirradiated adult recipients as a model for accelerated disease. Suppressor phenomena were detected by testing the protection afforded by lymphoid cells from nondiabetic NOD mice against diabetes transfer in irradiated recipients. Transfer of diabetes was delayed by reconstituting recipients with spleen cells from nondiabetic NOD donors. The greatest protection against diabetes transfer was conferred by spleen cells from 8-wk-old nondiabetic female NOD mice. Depletion experiments showed that the protection was dependent on CD4+ cells. Protection was also detected within thymic cells from nondiabetic NOD mice and protection conferred by spleen cells was abrogated by thymectomy of nondiabetic female, but not male, NOD donors at 3 wk of age. These findings indicate that suppressive CD4+ T cells that are dependent on the presence of the thymus may delay the onset of diabetes in female diabetes-prone NOD mice.
Animals↗
Acute HIV infection after acupuncture treatments.
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Acquired Immunodeficiency Syndrome↗
The majority of mouse spontaneous rosette-forming cells of thymic origin belong to the Ly-2+ subset.
Spontaneous sheep erythrocyte rosette-forming T cells (T-sRFC) found in normal mouse spleen are specific for the xenogeneic species of red cells and are distinct from human E rosettes as illustrated by their persistence after sheep red blood cell (SRBC) incubation with anti-LFA-3 monoclonal antibodies directed against SRBC molecule binding to the E rosette receptor. We confirm here using monoclonal antibodies that T-sRFC are Thy-1+CD3+. Additionally, using cell separation techniques based on panning and cell sorting, it is shown that the vast majority of spleen sRFC have the L3T4-Ly-2+ phenotype. As already shown for anti-Thy-1 antibodies, anti-CD3 and anti-Ly-2 antibodies block rosette formation, whereas antibodies to more abundant cell surface antigens (T200, H-2Db) are not inhibitory. These data suggest that the interaction of T-sRFC with SRBC occurs at or near the T cell receptor.
Animals↗
Neonatal induction of allogeneic tolerance prevents T cell-mediated autoimmunity in NOD mice.
Diabetes in the NOD mouse strain is a genetically programmed T cell-mediated autoimmune process that is directed against an as yet unknown antigen target(s) on pancreatic beta cells. To investigate whether the course of the autoimmune disease could be altered by immune manipulations of the T cell repertoire, we have induced allogeneic tolerance by injecting F1 semiallogeneic spleen cells into NOD neonates. This procedure resulted in a significant protection against both insulitis and diabetes. However, although it requires the induction of tolerance, as shown by the failure of non-tolerizing irradiated cells to prevent autoimmunity, protection appeared to be independent of the major histocompatibility complex haplotypes of the F1 spleen cells injected at birth, e.g. (C57BL/6 x NOD)F1, (CBA/Ca x NOD)F1 or (BALB/c x NOD)F1 cells. In addition, a similar degree of protection was induced, whether the tolerant state, as assessed by mixed lymphocyte reaction studies in vitro, was of short duration, approximately 6 weeks, or lasted for more than 12 weeks. Putative veto or suppressor functions of chimeric T cells were ruled out, since mice tolerized with T cell-depleted F1 spleen cells were equally protected. We conclude that the expression of spontaneous T cell-mediated autoimmunity can be modulated by immune manipulations at birth. Whether the protection observed in the present experiments resulted from the production of one or several specific holes in the autoimmune T cell repertoire, i.e. cross-tolerance, or whether it resulted from nonspecific disturbances of the emerging T cell repertoire remains to be elucidated.
Age Factors↗
Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning.
The effect of thymectomy performed at weaning (3 weeks) and at 6-7 weeks of age on the incidence of diabetes was examined in the non-Obese diabetic (NOD) mouse, a spontaneous model of immunologically mediated insulin-dependent diabetes similar to human type I diabetes. When performed at weaning, thymectomy led to a dramatic increase in the incidence of diabetes in NOD females in comparison to sham-thymectomized animals. Conversely, no change in the incidence of the disease or the expression of insulitis was noted when thymectomy was performed in NOD males. When delayed beyond 6-7 weeks of age, thymectomy had no effect on NOD males and females. Flow cytometry analysis of spleen cells from intact mice and mice thymectomized at weaning or at 6-7 weeks of age demonstrated a significant depletion of the T cell subsets in both groups of thymectomized animals. These results indicate that the onset of diabetes in NOD mice is submitted to thymic regulation and that the T cell depletion induced by thymectomy at weaning accelerates the disease, an effect possibly due to the loss of some T cell-dependent suppressor mechanisms.
Age Factors↗
The VH gene sequences of anti-DNA antibodies in two different strains of lupus-prone mice are highly related.
The heavy and light chain V region sequences of an IgG anti-DNA autoantibody (PME77), derived from a lupus-prone (NZB x NZW)F1 mouse have been determined by mRNA sequencing. The V kappa gene segment belongs to the V kappa 1A gene sub-group and is found in several (NZB x NZW)F1 and MRL lpr/lpr anti-DNA antibodies, as well as in other antibodies of unrelated specificities. The VH gene segment appears to represent a unique gene or a subfamily of the large J558 VH gene family of the mouse, and is highly related to a germ-line sequence of a major anti-DNA idiotype (H130, IgM) of MRL mice. This anti-DNA-related VH segment has not been found, so far, to be expressed in antibodies with specificities for external or synthetic antigens; therefore, expression of such specificities may be regulated by powerful mechanisms of self tolerance in the healthy animal. In addition, both the heavy and light chain of the PME77 IgG antibody were found to contain somatic point mutations with a high ratio of replacement to silent mutations in complementarity determining regions. This IgM to IgG sequence relationship suggests an affinity maturation process, which is driven by the autoantigen.
Amino Acid Sequence↗
Syngeneic T cell transfer of diabetes into NOD newborn mice: in situ studies of the autoimmune steps leading to insulin-producing cell destruction.
To overcome the limitations of in situ studies during the chronic spontaneous autoimmune process leading to insulin cell destruction and diabetes in non-obese diabetic (NOD) mice, we have developed a model of acute transfer of diabetes into healthy syngeneic newborns. The injection of 20 x 10(6) T cells from adult diabetic mice produced synchronous insulitis within 3 weeks and diabetes within 4-5 weeks in young recipients, at a time when non-injected control mice do not even exhibit histological changes in their pancreases. Sequential studies of pancreases from T cell-transferred mice showed that lymphoid infiltration was preceded by a strong tissue expression of Ia antigen which was restricted to the vessel-associated cells limiting the islet of Langerhans, and which might play a role in the recruitment of circulating T cells inside the islets. Acute destruction of most of the insulin-producing cells, leading to diabetes, could take place within a few days after insulitis had begun. A majority of the inflammatory cells were T lymphocytes, approximately 30% of which expressed interleukin 2 receptors. L3T4+ T cells largely predominated at the early phase of islet invasion whereas the proportion of Ly-2+ T cells substantially increased later when beta cell destruction occurred. In contrast, only a minority of B cells and macrophages participated to the inflammatory process. These data are in keeping with previous demonstrations that both T cell subsets contribute to the autoimmune disease. Furthermore, they suggest that beta cell injury is mediated through a cytotoxic process, which requires the sequential involvement of L3T4+ (helper) and Ly-2+ (cytotoxic) T cells.
Animals↗
Thymulin, a zinc-dependent hormone.
Thymulin (formerly called FTS) is a well defined nonapeptide hormone produced by thymic epithelial cells. Its biological activity and antigenicity depend upon the presence of the metal zinc in the molecule. This pharmacologically active metallopeptide induces the differentiation of T-cells and enhances several functions of the various T-cell subsets in normal or partially thymus-deficient recipients. Its effect on suppressor T-cells is, so far, the most remarkable and should be the first to find useful clinical applications. The peptide is a natural hormone, available in synthetic form. It is not toxic and one may foresee its clinical use as one of the major immunoregulatory agents in the near future.
Animals↗
Male BXSB mice develop a thymic hormonal dysfunction with presence of intraepithelial crystalline inclusions.
The thymus is morphologically abnormal in male BXSB mice with cortical involution densification of the epithelium and the presence of intraepithelial crystals. The thymic endocrine function in BXSB mice was appraised using a biological assay to measure the level of the zinc-dependent thymic hormone, thymulin, and an indirect immunofluorescence technique to evaluate the number of cells synthesizing the hormone within the thymus. Unlike the dramatically accelerated age-linked decline of thymulin production reported in females of other autoimmune strains (measured as early as 6 weeks of age), only male BXSB were affected, as compared to normal strains. The number of hormone-producing cells was significantly reduced in male BXSB thymuses, in parallel with this hormonal decrease. Thymulin inhibitory molecules were detected in male BXSB sera, as early as 8 weeks of age, as evaluated by their capacity to absorb in vitro and in vivo the biological activity of the hormone. These inhibitors are thymus dependent since they disappear after adult thymectomy. They are low MW molecules (less than 10 kDa), as previously found in normal aging mice, rather than autoantibodies, as evidenced in two autoimmune strains (B/W and db/db mice). These findings demonstrate that male BXSB mice develop thymic abnormalities very similar to those observed in other autoimmune strains. The presence of intrathymic crystals and of low MW inhibitors suggests the role of abnormal storage and the excretion of thymulin. This thymic dysfunction may play a role in the maintenance of B cell hyperactivity previously shown in BXSB males.
Aging↗
Thymic hormones and prostaglandins. I. Lack of stimulation of prostaglandin production by thymic hormones.
Prostaglandins (PGs) have been implicated as possible mediators of the biological activity of thymic hormones. It has been shown that type E-PGs are able to mimic the action of several thymic hormones and that indomethacin prevents in vivo or in vitro the appearance of Thy-1+ antigen induced by some of these factors. We thus investigated a possible role for PGs in the mechanism of action of different thymic extracts and peptides. Attempts to modulate prostaglandin production showed that neither thymosin fraction 5 (0.01-100 micrograms/ml), nor thymosin alpha 1 (1-10 micrograms/ml), thymulin (0.001-100 ng/ml), thymopoietin II (10-1000 ng/ml) or TP5 (10-1000 ng/ml) affect PGE2, 6-keto-PGF1 alpha, PGF2 alpha and TXB2 production by spleen cells from control and thymectomized mice. These results do not support the hypothesis that prostaglandins could act as mediators of thymic hormones.
Animals↗
Alpha-bungarotoxin blocking antibodies in neonatal myasthenia gravis: frequency and selectivity.
We have studied antibodies to the acetylcholine receptor (AChR) that inhibit alpha-bungarotoxin binding in 22 mothers with myasthenia gravis (MG) and in their 23 newborns. Of the 13 showing neonatal MG, seven of the mothers had detectable direct blocking antibodies, all 13 had decamethonium-dependent (DC) blocking, and nine had high titres of precipitating antibodies (greater than 40 nM). In those with symptom-free newborns, the corresponding figures were 2/10, 8/10 and 2/10; the mean titres of DC blocking and of precipitating antibodies were 5- and 3-fold lower than in the mothers of affected babies. Thus, blocking antibodies, in addition to high total antibody levels, may help to predict the occurrence of neonatal MG. However, the antibodies appear not to cross the placenta to the same extent in each case. 86, 69 and 84% of the maternal antibodies with precipitating, direct and DC blocking activities, respectively, were found in the myasthenic neonates versus 65, 28 and 44% in the unaffected. These data suggest (1) involvement of blocking antibodies in the pathogenesis of MG, and (2) variable placental transfer of anti-AChR antibodies, which makes neonatal affliction more difficult to predict.
Autoantibodies↗
The role of class II major histocompatibility complex antigens in autoimmune diabetes: animal models.
Like human insulin-dependent diabetes, autoimmune diabetes in BB rats and NOD mice is under control of Class II genes of the major histocompatibility complex. The mechanisms of expression of these genes is still unclear. No aberrant expression of Class II antigens was found in BB rats at the onset of diabetes. The putative role of inadequate Class II-linked suppressor control is suggested, however, by the observation that in vivo treatment with anti-Class II monoclonal antibody prevents the onset of diabetes in NOD mice, and that this protection can be transfer by CD4+ T cells.
Animals↗
Molecular and genetic characteristics of pathogenic autoantibodies.
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Animals↗
In vivo T cell preactivation in chronic uremic hemodialyzed and non-hemodialyzed patients.
The production and targeting of a major T cell derived lymphokine, Interleukin 2 (IL-2), were studied in 23 uremic patients undergoing regular hemodialysis treatment and 20 uremic patients prior to the onset of renal replacement therapy. In hemodialyzed patients, abnormally increased proportions of circulating T cells spontaneously expressing high affinity IL-2 receptors (IL-2 Rec) were detected: they bound a monoclonal antibody specifically directed to the IL-2 Rec 55 kDa chain (Tac antigen) (mean +/- SEM: 7.12 +/- 0.81% in patients vs. 2.15 +/- 0.39% in normal controls, P less than 0.0001) and significantly proliferated in presence of human recombinant IL-2 alone (mean +/- SEM: 5438 +/- 729 cpm in patients vs. 1647 +/- 244 cpm in normal controls). Hemodialyzed patients also exhibited significantly increased serum levels of soluble IL-2 receptor (mean +/- SEM: 4036 +/- 947 U/ml in patients vs. 253 +/- 29 U/ml in normal controls. P less than 0.001). Moreover, a significantly decreased IL-2 activity was detected in the supernatants of stimulated T cells from hemodialyzed patients (mean +/- SEM: 0.93 +/- 0.12 U/ml in patients vs. 2.49 +/- 0.22 U/ml in normal controls, P less than 0.0001). In nine hemodialyzed patients who were analyzed before and immediately after the hemodialysis session no acute modifications of the various parameters analyzed were detected. Although less profound, a similar pattern of T cell abnormalities was observed in the uremic non-hemodialyzed patients studied.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A monoclonal anti-double-stranded DNA autoantibody binds to a 94-kDa cell-surface protein on various cell types via nucleosomes or a DNA-histone complex.
A crude supernatant of hybridoma secreting a monoclonal anti-double-stranded (ds)DNA antibody (PME77 mAb), used to stain fibroblasts (CVI cells) in immunofluorescence, gives a punctuated staining of variable intensity. We had suggested that anti-DNA antibodies bind to cell-surface protein(s) of several cells. When the mAb of this crude supernatant was purified on a dsDNA-cellulose column and a histone-Trisacryl column, the mAb no longer bound to the cell surface. Only when dsDNA plus purified histones was added to the purified antibody did the immune complex strongly and uniformly stain again the cell surface of CVI cells. No significant staining was observed if either DNA or histones were omitted. A signal 94-kDa protein from membrane fractions of CVI, Raji, and RINm cell lines was visualized in immunoblots when mAb-DNA-histone complexes were applied to the nitrocellulose strips. No polypeptide was seen if one component was omitted. This 94-kDa protein behaved like a plasma membrane protein since it required the use of detergent to be solubilized and was quantitatively recovered in the Triton X-114 detergent-rich phase. Moreover, a brief treatment of living cells with trypsin cleared off this protein. Purified nucleosomes could be substituted to DNA-histone complexes, giving rise to identical results. Finally, purified polyclonal anti-DNA antibodies from sera of systemic lupus erythematosus patients labeled a 94-kDa protein provided that DNA-histone complexes were added. Anti-DNA autoantibodies could be pathogenic when they are bound to nucleosomes.
Animals↗
Suppression of the humoral response to anti-CD3 monoclonal antibody.
Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145-2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival--and, in some instances, resulted in a lethal anaphylactic reaction. In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.
Animals↗