Comparison of a classical Th1 bacteria versus a Th17 bacteria as adjuvant in the induction of experimental autoimmune encephalomyelitis.
ABSTRACT The relative contribution of myelin-specific Th1 and Th17 cells in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), is controversial. IL-12, the key cytokine necessary for the differentiation of Th1 cells, has been found to be dispensable for EAE induction; while the related cytokine associated with Th17 cells, IL-23, is a critical factor for inducing EAE. Since EAE is induced by immunization with myelin proteins in CFA which contains M. tuberculosis that generates a prototypical Th1-mediated immune response, we sought to determine if replacing the M. tuberculosis in the adjuvant with a bacterium that induces an IL-23-dependent Th17 cell response during infection would induce EAE with a different phenotype. C. rodentium, a bacterium that requires IL-23 for protective immunity, was used as the adjuvant in EAE and compared to CFA. Mice immunized with C. rodentium adjuvant (CRA) developed classical signs of EAE, similar to CFA-immunized mice, but disease was less severe with a later onset and slower progression than CFA. Surprisingly, the peripheral cytokine profile revealed similar numbers of Th1 and Th17 cells for both CFA and CRA-immunized mice; however, the number of Th1 and Th17 cells was significantly reduced in the CNS of CRA-immunized mice. The development of EAE in CRA-immunized mice was associated with epitope spreading. The unique clinical course of CRA immunizations helps serve as a useful alternative model for studying EAE pathogenesis and potential therapeutics for MS.
Article: THE RAPID PRODUCTION OF ACUTE DISSEMINATED ENCEPHALOMYELITIS IN RHESUS MONKEYS BY INJECTION OF HETEROLOGOUS AND HOMOLOGOUS BRAIN TISSUE WITH ADJUVANTS.[show abstract] [hide abstract]
ABSTRACT: 1. A picture resembling acute disseminated encephalomyelitis in the human being has been regularly and rapidly produced in rhesus monkeys by injection of emulsions of adult rabbit and monkey brain administered with adjuvants. 2. No lesions of the central nervous system resulted from injection of similar emulsions of fetal rabbit brain or adult rabbit lung. 3. A description of the gross and histological findings in the central nervous system is given and compared with features of human demyelinating disease. 4. The experimental findings are in accord with the hypothesis that antibody to the injected brain emulsion reacts with the tissues of the nervous system of the animal to produce the pathological changes.Journal of Experimental Medicine 01/1947; 85(1):117-30. · 13.85 Impact Factor
Article: ALLERGIC ENCEPHALOMYELITIS IN MONKEYS IN RESPONSE TO INJECTION OF NORMAL MONKEY NERVOUS TISSUE.[show abstract] [hide abstract]
ABSTRACT: By subcutaneous injection of central nervous tissue emulsified with adjuvants according to Freund's technique it has been possible to induce in the majority of monkeys an acute disseminated encephalomyelitis which is interpreted as an isoimmunization to CNS tissue. Positive reactions occurred only in response to CNS tissue containing white matter; i.e., cerebral white matter, spinal cord (whether normal or poliomyelitis-infected), and cortical "gray" matter (with an estimated 10 per cent contamination with white matter). No reaction occurred when peripheral nerve or kidney suspension or saline alone was injected with adjuvants. The perivascular and extravascular infiltration induced was confined to the CNS.Journal of Experimental Medicine 01/1947; 85(1):131-40. · 13.85 Impact Factor
Article: Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.[show abstract] [hide abstract]
ABSTRACT: IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23-dependent, pathogenic T cells produced IL-17 A, IL-17 F, IL-6, and TNF but not IFN-gamma or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti-IL-23p19-specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti-IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti-IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.Journal of Clinical Investigation 06/2006; 116(5):1317-26. · 15.39 Impact Factor