The Th1/Th2 Switch as a Possible Treatment Strategy for Crohn’s Disease

1. The Th1/Th2 Switch as a Possible Treatment Strategy for Crohn’s Disease Kwan Lee Christine Chiang Vinay Mahajan BE.214 2/24/2003

2. CD IFN, IL-2, IL-12, IL-18, and TNF : Th1 response UC IL-5, IL-6, IL-10, and IL-13 : Th2 response Regulation of Th cell differentiation and activities is a key for Therapy for inflammatory bowel diseases (IBD) Distinct pathways of inflammation in Crohn’s disease (CD) and ulcerative colitis (UC) : Different patterns of cytokines Gastroenterology, 123, 2140-2144 (2002)

3. Differentiation of type 1 helper T cells (Th1) Tumor necrosis factor Interleukin-1 Interleukin-6 Nature Reviews : Immunology, 2, 933-943 (2002) / N Engl J Med, 347, 417-429 (2002)

4. Immune regulation by IL-10 and TGF-beta Trends in Immunology, 23, 450-455 (2002)

5. Cytokine Inhibitors and Recombinant Cytokines as Treatment Options • Humanized anti-IFN-γAntibody (Phase II/III) • Humanized anti-IL-12 Antibody (Preclinical) • RhuIL-10 (Preclinical; Randomized Controlled Trials) – good for short term • TNFα Inhibition: • Humanized Antibody (CDP-571) • Soluble Receptors (Etanercept and TBP-1) • Chimeric Monoclonal Antibody (Infliximab) • Most clinically effective in symptom relief and remission

6. Cytokine Inhibitors and Recombinant Cytokines as Treatment Options • Apply case of Infliximab to other cytokine targets • Antibody can inhibit the activity • Chimeric antibody may be better than humanized • Generates an antibody-mediated cytotoxic response to cells producing the target cytokine (Th2 response) • Possible source of Th1/Th2 switch

7. ExperimentalTrichinella spiralis infection protects against colitis is mice. • ISSUES • which nematode and which part of the life cycle to choose • attenuated forms • public health concerns. • genomic/molecular data for nematodes extensive only for C. elegans. • Parasite antigens instead of organism • Public acceptance Use of parasite infection as therapy is not new. Malaria Rx neurosyphilis. J. Wagner von Jauregg – Nobel prize 1927. Malariotherapy used to treat Lyme disease. Discontinued after etiology-based treatment became available. Is “empirical therapy” acceptable for a disease for which pathology is known but not the etiology? “Hygeine hypothesis” – studies on immigrants from Crohn’s - free zones. Fact: In India, IBD is rare. Crohn’s is rarer. UC is the predominant form of IBD seen.

8. Many links between innate and adaptive immunity. Macrophages, Mast cells, Eosinophils, Neutrophils, Catalytic antibodies,… HYPOTHESIS: Th1/Th2 polarization is biased by the innate response. The body doesn’t just tolerate commensals. The commensals are adapted to evade the immune response. • Probiotics – delivering the ‘right’ commensals to the gut. http://www.vslpharma.com/vsl3/probiotics.htm • (e.glactobacilli, streptococci, bifidobacteria) • Genetically altered microbial flora. • Genetically modified to express Th2 type cytokines (IL10) • “Biologic” expressed under inducible promoter. controlled activation. controlled dose termination. • Gene therapy of the commensal flora. eg. F+ Plasmid vector • Delivery of antibodies via expression by gut flora tolerogenic ?? & No need to humanize ??

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