Vedolizumab (anti-integrin) is effective for treatment of ulcerative colitis and Crohn's disease

The integrin superfamily consists of 30 proteins that promote cell-cell or cell-matrix interactions. The name integrins derives from the idea that they coordinate (i.e., "integrate") signals.

All integrins are cell surface proteins composed of 2 polypeptide chains, α and β. Integrins are classified into several subfamilies based on the β chains.



Lymphocyte Trafficking. This video describes how lymphocytes travel through the blood stream and into a lymph node. This video is from: Janeway's Immunobiology, 7th Edition, Murphy, Travers, & Walport. Source: Garland Science.

7 Integrin, a cell adhesion molecule, is present in the form of α4β7 integrin or αEβ7 integrin. α4β7 Integrin is expressed on most leucocytes and is essential for their migration to gut-associated lymphoid tissues by interacting with its primary ligand, mucosal addressin cell adhesion molecule-1, which is preferentially expressed in gut-associated lymphoid tissues.

Vedolizumab is a monoclonal antibody being developed by a subsidiary of Takeda Pharmaceuticals for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin α4β7 (LPAM-1, lymphocyte Peyer's patch adhesion molecule 1). Blocking the α4β7 integrin results in gut-selective anti-inflammatory activity by blockade of lymphocyte trafficking.

Sunanda Kane, M.D., a gastroenterologist at Mayo Clinic specializing in the care and evaluation of patients with IBD, discusses two articles recently published in NEJM that found patients with ulcerative colitis or Crohn's disease benefited from treatment with vedolizumab compared with placebo. She discusses how vedolizumab is different than other drugs currently used to treat IBD.



Recruitment of Leukocytes to Sites of Infection can be remembered by the mnemonic: "SIP of wine":

Selectins
Integrins
Penetration of of the basement membrane (BM) by PMN

Selectins are first in the chain of events. They upregulate TNF and IL-1. Integrins cause release of VCAM and VLA.

Adhesion molecules, 3 groups are remembered by the mnemonic SIS:

Selectins
Integrins
Superfamily Ig

References:

http://www.ncbi.nlm.nih.gov/pubmed/21047673
http://www.nejm.org/doi/full/10.1056/NEJMe1307415
http://www.nejm.org/doi/full/10.1056/NEJMoa1215739
http://www.nejm.org/doi/full/10.1056/NEJMoa1215734

Drug companies trying to "create" parasites for treating ulcerative colitis

Ulcerative colitis, a type of inflammatory bowel disease (IBD), is less common in countries endemic for helminth infections, suggesting that helminth colonization may have the potential to regulate intestinal inflammation in IBD. Therapeutic effects of experimental helminth infection have been reported.

According to a researcher: "What we found was that after worm infection, the regions of the colon that were previously not making mucus, were now making mucus again."

"That's a key factor in healing, and it looked like the mucus came back because the worms were causing the body to produce IL-22. This is a molecule that promotes epithelial growth and healing."

Studies suggest parasites can regulate the immune system in ways that prevent it from "going wild" and attacking healthy tissue, and possibly human evolution took that into account.

A case report in the journal Science Translational Medicine provides a cellular and molecular portrait of dynamic changes in the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of ulcerative colitis.

Tissue with active colitis had a prominent population of mucosal T helper (TH) cells that produced the inflammatory cytokine interleukin-17 (IL-17) but not IL-22, a cytokine involved in mucosal healing.

After helminth exposure, the disease went into remission, and IL-22–producing TH cells accumulated in the mucosa. Genes involved in carbohydrate and lipid metabolism were up-regulated in helminth-colonized tissue, whereas tissues with active colitis showed up-regulation of proinflammatory genes such as IL-17, IL-13RA2, and CHI3L1.

T. trichiura colonization of the intestine may reduce symptomatic colitis by promoting goblet cell hyperplasia and mucus production through TH2 cytokines and IL-22. Controlled helminth infections may lead to new therapies for inflammatory bowel diseases.

References:

Eat Your Worms: The Upside Of Parasites. NPR.

M. J. Broadhurst, J. M. Leung, V. Kashyap, J. M. McCune, U. Mahadevan, J. H. McKerrow, P. Loke, IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient. Sci. Transl. Med. 2, 60ra88 (2010).

Helminth Trichuris suis (pig whipworm) had no effect as therapy for allergic rhinitis

Ulcerative Colitis - NEJM update, 2011.

Image source: Trichuris egg in stool sample (40x). Wikipedia, GNU Free Documentation License, Version 1.2.