Prevention of Diabetes in NOD Mice by Injection of Autoreactive T-Lymphocytes

Reich, E.; Scaringe, Denise; Yagi, Junji; Sherwin, Robert S.; Janeway, Charles A.

doi:10.2337/diab.38.12.1647

Cited by 43 publications

(10 citation statements)

References 19 publications

(15 reference statements)

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“…Because T-cell functions recover in 4-6 weeks after ALS treatment (18), a different mechanism must be involved in the maintenance of autoimmune-free conditions after ALS treatment. Previous studies in NOD mice have indicated that both lymphoid tissue and lymphoid cells infiltrating the islets contain autoreactive suppressor cells that are capable of inhibiting the development ofdiabetes (19,20). Although the precise nature of these suppressor cells has not been described, it is possible that these cells may be similar to the bone marrow-derived self-major histocompatibility complex antigen-reactive suppressor cells (veto cells), that may play an important role in establishing self-tolerance outside the thymus (21).…”

Section: Discussionmentioning

confidence: 99%

Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum.

Maki

Ichikawa

Blanco

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

101

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We investigated the therapeutic effect of antilnphocyte serum (ALS) on clinically overt diabetes by using a nonobese diabetic (NOD) Immunotherapy with ALS. ALS was obtained by immunizing rabbits with a pool of lymph node cells prepared from NOD, C3H/He, DBA/2, and (C57BL/6 x A)F1 mice (11). A 0.4-ml injection of ALS was given intraperitoneally to diabetic NOD mice on days 0 (the first day of treatment regardless of the duration of diabetes) and +2. Control mice were given 0.4 ml ofnormal rabbit serum (NRS) on days 0 and +2. Blood glucose levels were monitored every 2-3 days initially and once a week thereafter. Achievement of euglycemia (<11 mM) and independence from exogenous insulin treatment after immunotherapy was defined as clinical remission.Immunotherapy with Monoclonal Antibodis (mAbs). Hybridoma cells producing anti-CD4 (anti-L3T4, clone GK 1.5) mAb were kindly provided by Kevin J. Lafferty (Barbara Davis Center for Juvenile Diabetes, Denver). Hybridomas producing anti-CD8 (anti-Lyt 2.1, clone 116-13.1, and antiLyt 2.2, clone 41-3.48) mAb were obtained from American Type Culture Collection. Ascites fluid that contained mAbs at -5 mg/ml was used. Diabetic NOD mice were treated with anti-CD4 mAb at 0.2 ml on days 0, 7, 14, and 21 and/or 0.1 ml of anti-CD8 (anti-Lyt 2.1) mAb on days 0 and 14. This treatment protocol has been shown (12) to achieve long-term removal of CD4' and/or CD8+ T lymphocytes from peripheral lymphoid organs in other inbred mouse strains. Control diabetic NOD mice were treated with 0.2 ml of anti-Lyt 2.2 mAb on days 0, 7, 14, and 21.Flow Cytometric Analysis. Peripheral lymph node cells were stained with fluorescein isothiocyanate conjugates of mAb 53-6.7 (anti-CD8) and phycoerythrin-conjugates of mAb GK1.5 (anti-CD4), both of which were obtained from Becton Dickinson. Two-color analysis was performed with a singlebeam flow cytometer, FACScan (Becton Dickinson) and the FACSCAN Research Software (Becton Dickinson).Islet Isolation and Transplantation. Because insulitis generally starts at 4 weeks of age (1), NOD islet donors were Abbreviations: NOD, nonobese diabetic; ALS, anti-lymphocyte serum; NRS, normal rabbit serum; mAb, monoclonal antibody.tTo whom reprint requests should be addressed at: CRI, New

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Section: Discussionmentioning

confidence: 99%

Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum.

Maki

Ichikawa

Blanco

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

101

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“…Both CD4+ Th, and noncytotoxic CD8+ T-lymphocyte clones have been isolated from NOD mouse islets that can prevent diabetes when injected back into susceptible NOD recipients (27,28). Furthermore, similar cotransfers of spleen cells from diabetic and young nondiabetic donors result in protection from diabetes in the recipients (29).…”

Section: Discussionmentioning

confidence: 99%

Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.

Muir¹,

Peck²,

et al. 1995

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We reported previously that daily injections of isophane insulin prevented both hyperglycemia and insulitis in nonobese diabetic (NOD) mice and R. Luchetta. 1990. . The possible mechanisms responsible include reduced immunogenicity of pancreatic fl-cells from ",B-cell rest" and induced active immunoregulation to insulin (Aaen, K., J. Rygaard, K. Josefsen, H. Petersen, C. H. Brogren, T. Horn, and K. Buschard. 1990. Diabetes. 39:697-701). We report here that intermittent immunizations with insulin or its metabolically inactive B-chain in incomplete Freund's adjuvant also prevent diabetes in NOD mice, whereas immunizations with A-chain insulin or with BSA do not. Adoptive transfer of splenocytes from B-chain insulin-immunized mice prevented diabetes in recipients co-infused with diabetogenic spleen cells, an effect that was abolished by prior in vivo elimination of either CD4+ or CD8+ cells. Insulin immunization did not reduce the extent of intraislet inflammation (insulitis); however, it did abolish expression of IFN-y mRNA within the insulitis lesions. Immunizations with insulin thus induce an active suppressive response to determinants on the B-chain that converts the insulitis lesion from one that is destructive to one that is protective. (J. Clin. Invest. 1995. 95:628-634.)

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“…For antigenic stimulation, cells were exposed every 3 wk to irradiated (2000 rad) NOD-derived pancreatic islets or NOD splenocytes loaded with 0.01 mg/ml synthetic peptide derived from mouse insulin B chain, amino acids 15-23 (LYLVCGERG) (28), produced by Research Genetics (Huntsville, AL). Pancreatic islets were isolated by collagenase inflation method, as described (30), and handpicked in HBSS (Life Technologies) after purification on Histopaque 1119 (Sigma-Aldrich) gradient (31).…”

Section: Insulin-specific Cd8mentioning

confidence: 99%

IFN-γ Affects Homing of Diabetogenic T Cells

Savinov

Wong

Chervonsky

2001

The Journal of Immunology

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IFN-γ is a cytokine with pleiotropic functions that participates in immune and autoimmune responses. The lack of IFN-γ is known to delay the development of autoimmune diabetes in nonobese diabetic (NOD) mice. Splenocytes from diabetic NOD and IFN-γ knockout (KO) NOD mice transfer diabetes into NOD recipients equally well. However, adoptive transfer of diabetogenic T cells from NOD mice into NOD.IFN-γ-KO or NOD mice lacking β-chain of IFN-γ receptor (NOD.IFN-γRβ-KO) appeared to be much less efficient. We found that IFN-γ influences the ability of diabetogenic cells to penetrate pancreatic islets. Tracing in vivo of insulin-specific CD8+ T cells has shown that homing of these cells to the islets of Langerhans was affected by the lack of IFN-γ. While adhesion of insulin-specific CD8+ cells to microvasculature was normal, the diapedesis was significantly impaired. This effect was reversible by treatment of the animals with rIFN-γ. Thus, IFN-γ may, among other effects, influence immune and autoimmune responses by supporting the homing of activated T cells.

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Prevention of Diabetes in NOD Mice by Injection of Autoreactive T-Lymphocytes

Cited by 43 publications

References 19 publications

Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum.

Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum.

Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.

IFN-γ Affects Homing of Diabetogenic T Cells

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