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The Th1/Th2 Switch as a Possible Treatment Strategy for Crohn’s Disease. Kwan Lee Christine Chiang Vinay Mahajan BE.214 2/24/2003. CD IFN, IL-2, IL-12, IL-18, and TNF : Th1 response UC IL-5, IL-6, IL-10, and IL-13 : Th2 response.

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the th1 th2 switch as a possible treatment strategy for crohn s disease

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

Kwan Lee

Christine Chiang

Vinay Mahajan

BE.214

2/24/2003

slide2

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)

differentiation of type 1 helper t cells th1
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)

immune regulation by il 10 and tgf beta
Immune regulation by IL-10 and TGF-beta

Trends in Immunology, 23, 450-455 (2002)

cytokine inhibitors and recombinant cytokines as treatment options
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
cytokine inhibitors and recombinant cytokines as treatment options6
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
slide7

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.

slide8
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 ??
references
References
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  • Andoh A, Bamba T. [Treatment of Crohn's disease by anti-cytokine monoclonal antibodies] Nippon Rinsho. 2002 Jan;60(1):117-22. Review. Japanese.
  • Berg DJ, Zhang J, Weinstock JV, Ismail HF, Earle KA, Alila H, Pamukcu R, Moore S, Lynch RG. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology. 2002 Nov;123(5):1527-42.
  • Caprilli R, Viscido A, Guagnozzi D. Review article: biological agents in the treatment of Crohn's disease. Aliment Pharmacol Ther. 2002 Sep;16(9):1579-90. Review.
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  • Gastroenterology, 123, 2140-2144 (2002)
  • http://www.pdl.com/wt/sec.php3?page_name=products
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  • Parronchi P, Romagnani P, Annunziato F, Sampognaro S, Becchio A, Giannarini L, Maggi E, Pupilli C, Tonelli F, Romagnani S. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol. 1997 Mar;150(3):823-32.
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