Acute Shock Induced by Antigen Vaccination in NOD Mice
- Lut Overbergh1,
- Brigitte Decallonne1,
- Dumitru D. Branisteanu2,
- Dirk Valckx1,
- Ahmad Kasran3,
- Roger Bouillon1 and
- Chantal Mathieu1
- 1Laboratory for Experimental Medicine and Endocrinology (LEGENDO), University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
- 2Clinic of Endocrinology, University Hospital “St. Spiridon,” University of Medicine and Pharmacy “Gr. T. Popa,” Iasi, Romania
- 3Laboratory for Immunology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
Abstract
Type 1 diabetes in NOD mice can be prevented through autoantigen vaccination by shifting lymphocyte differentiation toward a T-helper 2 (Th2) response. However, in other models of autoimmunity, this approach may be accompanied by unexpected triggering of Th2-dependent anaphylactic shock. To test the safety of vaccination therapy in the NOD mouse model, we evaluated the effects of immunization with a wide battery of antigens in NOD, BALB/c, and C57BL/6 mice. Surprisingly, a nondiabetogenic antigen, hen egg white lysozyme, induced severe shock exclusively in NOD mice (shock in 11 of 11 mice, lethal in 3 mice). Shock severity was further increased by a more pronounced Th2 setting generated by 1α,25(OH)2D3 administration (17 of 17 mice, lethal in 14 mice, P < 0.0001). Pretreatment with dexamethasone resulted in full rescue, indicating an immune-mediated mechanism. Serum IgE levels and Th1/Th2 cytokine profile analysis showed that the shock phenomenon was paralleled by a Th2 response. mRNA expression of platelet-activating factor receptor (PAF-R) was significantly higher in NOD mice (P < 0.01) and was further increased by 1α,25(OH)2D3. Pretreatment with WEB2086 (PAF-R antagonist) again protected all mice from lethal shock, indicating PAF as an anaphylaxis effector. In conclusion, in NOD mice, vaccination leading to a Th2 immune shift can result in a lethal anaphylactic reaction.
Footnotes
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Address correspondence and reprint requests to Chantal Mathieu, MD, LEGENDO, Universitair Ziekenhuis Gasthuisberg, Onderwijs en Navorsing niveau 9, Herestraat 49, B-3000 Leuven, Belgium. E-mail: chantal.mathieu{at}med.kuleuven.ac.be.
Received for publication 13 May 2002 and accepted in revised form 5 November 2002.
L.O. and B.D. contributed equally to this work.
AH, acetylhydrolase; CFA, complete Freund’s adjuvant; EAE, encephalomyelitis; ELISA, enzyme-linked immunosorbent assay; HEL, hen egg white lysozyme; hsp, heat shock protein; IFN-γ, γ-interferon; IL, interleukin; ins-B, insulin B; KLH, keyhole limpet hemocyanine; MS, multiple sclerosis; OVA, ovalbumin; PAF-R, platelet-activating factor receptor; Th1, T-helper 1; TNF, tumor necrosis factor; TT, tetanus toxin.
- DIABETES
