Preventive effect of monoclonal anti-L3T4 antibody on development of diabetes in NOD mice

Koike, Takao; Itoh, Y.; Ishii, Toshiharu; Ito, Isao; Takabayashi, Katsuhiko; Maruyama, N.; Tomioka, Hisao; Yoshida, Sho

doi:10.2337/diabetes.36.4.539

Cited by 128 publications

(63 citation statements)

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“…These findings are consistent with several other studies in which anti-CD4 antibodies were successfully used either to retard, prevent or reverse the clinical and immunological manifestations of several murine models of autoimmune diseases such as diabetes in NOD mice [14,20,21], collagen-induced arthritis in DBA/1 mice [15], systemic lupus erythematosus (SLE) in NZB/NZW F, [11,12] and BXSB mice [13], and chronic relapsing encephalomyelitis in SJL/J [16], In these long-term experiments we have used saline rather than an irrelevant rat MoAb since the experiments of Wofsy [23] with BXSB mice showed that mice receiving rat IgG over a long period died prematurely, presumably due to T-dependent anti-rat antibodies. This cannot occur when the T cells are compromised by the anti-CD4 specificity ofthe rat antibodies [13,18], In NZB mice, the autoimmune response has previously been .shown to be T cell-dependent in vitro [10].…”

Section: Discussionsupporting

confidence: 81%

“…Previous studies by others have shown the requirement of T cells for the production of erythrocyte autoantibodies [10], In a number of other experimental models of autoimmunity, antibodies to CD4 inhibit the development of the disease and/or even reverse ongoing disease [11][12][13][14][15][16]. Furthermore, treatment with the anti-CD4 MoAbs which do not deplete the CD4 population has also been shown to result in the induction of tolerance to soluble proteins [17,18] and to minor histocompatibility antigens when administered in combination with anti-CD8 [19].…”

Section: Introductionmentioning

confidence: 99%

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Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

Oliveira

Hutchings

Roitt

et al. 1994

Clinical and Experimental Immunology

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SUMMARYNZB mice spontaneously develop haemolytic anaemia as the result of production of erythrocyte autoantibodies. The mechanisms leading to breakdown in tolerance to erythrocyte autoantigens are unknown. Antibodies to CD4 have been successfully used to treat several murine models of autoimmune disease. In this study we injected NZB mice with non-depleting CD4 antibodies and were able to prevent and abrogate erythrocyte autoantibody production in young {Coombs" negative) and old (Coombs" positive) mice, respectively. Our data indicate the dependency of autoantibody production on CD4' T cells. However, withdrawal of anti-CD4 antibodies resulted in the appearance of erythrocyte autoantibodies, showing that under these conditions we were unable to re-establish tolerance to autoantigens on erythrocytes using anti-CD4 treatment.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

Oliveira

Hutchings

Roitt

et al. 1994

Clinical and Experimental Immunology

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“…The key roles of macrophages include the presentation of processed antigen to helper T-lymphocytes in the context of MHC class II molecules present on the surface of macrophages. Recent observations emphasized that L3T4 + helper T-lymphocytes play a role in the pathogenesis of diabetes in NOD mice (10,11). Administration of anti-L3T4 monoclonal antibody to NOD mice prevented the development of diabetes and the rejection of islet allografts.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Initial Involvement of Macrophage in Development of Insulitis in NOD Mice

1988

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Macrophages have been shown to be the major population of infiltrated immunocytes at the early stage of insulitis in diabetes-prone BB rats. This study was undertaken to investigate the role of macrophages in the development of insulitis in nonobese diabetic (NOD) mice. Administration of cyclophosphamide to NOD mice resulted in a significant increase in the incidence of overt diabetes and severity of insulitis compared with that in untreated NOD mice. Intraperitoneal injections of silica completely prevented the development of diabetes and insulitis in both cyclophosphamide-treated and untreated animals. Because silica is selectively toxic to macrophages, the results suggest that macrophages play an important role in the initiation of insulitis in NOD mice. Diabetes 37:989-91, 1988 E vidence indicates that many patients with insulindependent diabetes mellitus (IDDM) may result from an autoimmune process directed against pancreatic p-cells (1). Animal models for IDDM, such as BB rats and nonobese diabetic (NOD) mice, support the autoimmune hypothesis. However, the mechanism underlying the autoimmunity remains unknown (1). Various effector systems, e.g., T-lymphocytes, natural killer (NK) cells, macrophages, and/or humoral mediators, have been implicated as the possible effectors of immune responses.Recent studies from our laboratory and others revealed that most infiltrated immunocytes at the early stage of insulitis in BB rats are macrophages (2,3). These findings suggested that macrophages may be involved in the initiation of insulitis. We investigated whether macrophages have an initial permissive role in the immune response against pancreatic pcells in NOD mice. MATERIALS AND METHODSOur NOD mouse colony was produced from a breeding stock obtained from Clea Japan (Tokyo). These animals were maintained on regular rat chow and tap water ad libitum at the University of Calgary. Beginning at ~8 wk of age, their urinary glucose and ketone levels were determined twice weekly with Diastix and Ketostix reagent slips (Miles, Ontario, Canada). Individual mice were classified as diabetic on the basis of positive glycosuria. The overall cumulative incidence of diabetes among the colony was -1 5 % in males and 50% in females at 24 wk of age.A total of 32 male animals from 10 litters, divided into four groups (n = 8/group), were used for this study. We injected silica (Steinkohlen-Bergbau-Verein, Essen, FRG), at a dose of 200 mg • kg~1 body wt • wk~1 i.p., into one group of animals from 4 to 10 wk of age. The second group of animals received silica, as described above, and subsequently cyclophosphamide (Homer, Montreal, Canada), at a dose of 150 mg/kg body wt twice per 3-day interval, at age 10 wk. The third group received only cyclophosphamide, administered at a dose identical to the second group. The fourth group of animals received no chemicals and were used as controls.Two weeks after the second injection of cyclophosphamide, the mice were killed by suffocation with carbon dioxide, and their pancreases were fixed in 6% ...

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“…Efficacy of antLCD4 monoclonal antibody (MAb) therapy in several murine models, including collagen arthritis (lo), systemic lupus erythematosus (1 l), myasthenia gravis (12), experimental allergic encephalomyelitis (13), diabetes mellitus (14), thyroiditis ( 1 3 , and uveitis (16), strongly supports this view. Pilot studies using several murine MAbs directed against human CD4 in patients with refractory RA have yielded promising results (17)(18)(19)(20)(21).…”

mentioning

confidence: 91%

Use of a chimeric monoclonal anti‐CD4 antibody in patients with refractory rheumatoid arthritis

Moreland

Bucy

Tilden

et al. 1993

Arthritis & Rheumatism

127

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Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti‐CD4 (cM‐T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment.Methods. Twenty‐five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM‐T412 in an open‐label, escalating‐dose phase I trial.Results. Infusion with cM‐T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self‐limited and appeared to correlate with transient elevations in interleukin‐6. No significant human antibody response to the cM‐T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM‐T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM‐T412 infusion.Conclusions. Treatment of refractory RA with cM‐T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM‐T412 may have beneficial effects in these patients with refractory RA. A double‐blind clinical trial is warranted to determine its clinical efficacy in treating RA.

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Preventive effect of monoclonal anti-L3T4 antibody on development of diabetes in NOD mice

Cited by 128 publications

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Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

Evidence for Initial Involvement of Macrophage in Development of Insulitis in NOD Mice

Use of a chimeric monoclonal anti‐CD4 antibody in patients with refractory rheumatoid arthritis

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