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Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus.

von Herrath MG, Oldstone MB - J. Exp. Med. (1997)

Bottom Line: Odermatt, P.Ohashi, R.M.They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction.

View Article: PubMed Central - PubMed

Affiliation: Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA.

ABSTRACT
Autoimmune mediated destruction of beta cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their beta cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner, 1996, J. Exp. Med. 183:2143-2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction. Here we provide evidence that killing of beta cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-gamma (IFN-gamma)-deficient mice, beta cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-gamma and express LCMV NP or GP in their beta cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, beta cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-gamma, presumably through enhancement of major histocompatibility complex expression and antigen presentation.

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Incidence of IDDM  (blood glucose >300 mg/dl) in  RIP LCMV (NP or GP) IFN-γ– deficient or –competent tg mice.  Blood glucose levels were measured at 2-wk intervals as described  in Materials and Methods, 10  mice per group were analyzed.  LCMV-treated mice were challenged with 2 × 103 PFU  LCMV intraperitoneally.
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Figure 1: Incidence of IDDM (blood glucose >300 mg/dl) in RIP LCMV (NP or GP) IFN-γ– deficient or –competent tg mice. Blood glucose levels were measured at 2-wk intervals as described in Materials and Methods, 10 mice per group were analyzed. LCMV-treated mice were challenged with 2 × 103 PFU LCMV intraperitoneally.

Mentions: IDDM did not occur in RIP GP or NP 25-3 single tg mice unless they were challenged with LCMV ARM (Fig. 1). Fig. 1 also shows that 2–8 wk after receiving 1 × 105 PFU of LCMV intraperitoneally, most IFN-γ–competent RIP GP (fast-onset IDDM) or NP (slow-onset IDDM) single tg mice develop IDDM. In contrast, virus-inoculated double tg mice (10 mice/group) that were deficient in IFN-γ production did not develop IDDM over a 5–8-mo observation period. Thus, virus induced IDDM does not occur in the absence of IFN-γ, regardless of the affinity of the generated antiself (viral) CTLs.


Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus.

von Herrath MG, Oldstone MB - J. Exp. Med. (1997)

Incidence of IDDM  (blood glucose >300 mg/dl) in  RIP LCMV (NP or GP) IFN-γ– deficient or –competent tg mice.  Blood glucose levels were measured at 2-wk intervals as described  in Materials and Methods, 10  mice per group were analyzed.  LCMV-treated mice were challenged with 2 × 103 PFU  LCMV intraperitoneally.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196037&req=5

Figure 1: Incidence of IDDM (blood glucose >300 mg/dl) in RIP LCMV (NP or GP) IFN-γ– deficient or –competent tg mice. Blood glucose levels were measured at 2-wk intervals as described in Materials and Methods, 10 mice per group were analyzed. LCMV-treated mice were challenged with 2 × 103 PFU LCMV intraperitoneally.
Mentions: IDDM did not occur in RIP GP or NP 25-3 single tg mice unless they were challenged with LCMV ARM (Fig. 1). Fig. 1 also shows that 2–8 wk after receiving 1 × 105 PFU of LCMV intraperitoneally, most IFN-γ–competent RIP GP (fast-onset IDDM) or NP (slow-onset IDDM) single tg mice develop IDDM. In contrast, virus-inoculated double tg mice (10 mice/group) that were deficient in IFN-γ production did not develop IDDM over a 5–8-mo observation period. Thus, virus induced IDDM does not occur in the absence of IFN-γ, regardless of the affinity of the generated antiself (viral) CTLs.

Bottom Line: Odermatt, P.Ohashi, R.M.They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction.

View Article: PubMed Central - PubMed

Affiliation: Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA.

ABSTRACT
Autoimmune mediated destruction of beta cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their beta cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner, 1996, J. Exp. Med. 183:2143-2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction. Here we provide evidence that killing of beta cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-gamma (IFN-gamma)-deficient mice, beta cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-gamma and express LCMV NP or GP in their beta cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, beta cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-gamma, presumably through enhancement of major histocompatibility complex expression and antigen presentation.

Show MeSH
Related in: MedlinePlus