Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response.

Herrath, Matthias G. von; Allison, Janette; Miller, J. F. A. P.; Oldstone, Michael B. A.

doi:10.1172/jci117688

Cited by 51 publications

(25 citation statements)

References 41 publications

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“…Double transgenic RIP-E3 ϫ RIP-LCMV mice expressing both E3 and LCMV proteins in their ␤ cells were generated by mating H-2 b RIP-E3 with H-2 b RIP-LCMV transgenic mice. Offspring were tested by PCR analysis using LCMV and E3 primers, as described (5,16,17).…”

Section: Methodsmentioning

confidence: 99%

“…Tissues taken for histological analysis were fixed in 10% zinc formalin and stained with hematoxylin and eosin. Immunohistochemical studies were carried out on 6-to 10-m freshly frozen cryomicrotome sections (14,16) of the pancreas to detect expression of class I MHC, D b , CD4, and CD8. Primary antibodies were applied for 1 hr.…”

Section: Methodsmentioning

confidence: 99%

“…After washing in PBS, the secondary antibody [biotinylated goat anti-rat (or anti-mouse) IgG͞Vector Laboratories] was applied for 1 hr. Color reaction was developed with sequential treatment using avidin-horseradish peroxidase conjugate (Boehringer Mannheim) and diaminobenzidinehydrogen peroxide (16,17).…”

Section: Methodsmentioning

confidence: 99%

“…To determine CTL activity after secondary stimulation, spleen cells or lymphocytes from the pancreas harvested from mice 60 days after primary inoculation with 1 ϫ 10 5 pfu͞0.1 ml saline LCMV i.p. were incubated with MHC-matched, irradiated, LCMV-infected macrophages in the presence of T cell growth factor and irradiated syngeneic spleen feeder cells for 5 days (16,17).…”

Section: Methodsmentioning

confidence: 99%

“…Lymphocytes were isolated from the pancreas as described (16,17). Briefly, tissues obtained from transgenic mice were freed from fat and surrounding lymphoid tissue.…”

Section: Methodsmentioning

confidence: 99%

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Expression of adenoviral E3 transgenes in β cells prevents autoimmune diabetes

Herrath

Efrat

Oldstone

et al. 1997

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

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The adenovirus (Ad) genome contains immunoregulatory and cytokine inhibitory genes that are presumed to function in facilitating acute infection or in establishing persistence in vivo. Some of these genes are clustered in early region 3 (E3), which contains a 19-kDa glycoprotein (gp19) that inhibits the transport of selected class I major histocompatibility complex (MHC) molecules out of the endoplasmic reticulum. In addition, the E3 region contains three protein inhibitors of the cytolytic function of tumor necrosis factor ␣ (TNF-␣). Because type I autoimmune diabetes destroys islets by mechanisms that involve class I MHC and TNF-␣, we investigated whether the entire cassette of Ad E3 genes might prevent the onset of diabetes in a well studied lymphocytic choriomeningitis viral (LCMV) murine model of virus-induced autoimmune diabetes. In this model, a LCMV polypeptide (either glycoprotein or nucleoprotein) expressed as a transgene in the islets is a target for autoimmune destruction of ␤ cells after LCMV infection. In this scenario the LCMV-induced immune response is directed not only against the virus but also against the LCMV transgenes expressed in the ␤ cells. Our experiments demonstrated a very efficient prevention of this LCMV-triggered diabetes by the Ad E3 genes. This resulted from the inhibition of target cell recognition by a fully competent and LCMV-primed immune system. Unlike the results from the ␤-2 microglobulin gene deletion experiments, our approach shows that selective regulation at the level of the target cell is sufficient to prevent autoimmune diabetes without disrupting the function of the systemic immune response. Although the Ad genes in these experiments were provided as transgenes, recent experiments may permit the introduction of such genes through the use of viral vectors. Although the decrease in class I MHC in islets by Ad genes was demonstrated in these in vivo studies, the relative importance of this process and the control of TNF-␣ cytolysis must await further genetic dissection of the introduced Ad genes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Lymphocytes were isolated from the pancreas as described (16,17). Briefly, tissues obtained from transgenic mice were freed from fat and surrounding lymphoid tissue.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Expression of adenoviral E3 transgenes in β cells prevents autoimmune diabetes

Herrath

Efrat

Oldstone

et al. 1997

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

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The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice

DiPaolo

Unanue

2001

Eur. J. Immunol.

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We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 T cell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52 – 61 family of hen egg‐white lysozyme (HEL) peptides in the context of MHC class II I‐Ak molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64 % of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peri‐pancreatic nodes have a large contentof peptide‐MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26‐fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100‐fold more peptide‐MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide‐MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the developmentof autoimmunity.

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The Function of TGF-β-Mediated Innocent Bystander Suppression Associated with Physiological Self-tolerancein Vivo

Teng

Gorczynski

Hozumi

1998

Cellular Immunology

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Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response.

Abstract: The participation of IL-2 in insulin-dependent ( Invest. 1995. 95:477-485.)

Cited by 51 publications

References 41 publications

Expression of adenoviral E3 transgenes in β cells prevents autoimmune diabetes

Expression of adenoviral E3 transgenes in β cells prevents autoimmune diabetes

The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice

The Function of TGF-β-Mediated Innocent Bystander Suppression Associated with Physiological Self-tolerancein Vivo

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