Request for international collaboration supported by the IRTA - Genetic Mutations in Intestinal Transplantation (GEM-IT)

irta leuven

Organising center:
Leuven Intestinal Failure and Transplantation Center; University Hospitals Leuven, Belgium
Laurens J. Ceulemans; Emilio Canovai; Tim Vanuytsel; Jacques Pirenne
Herestraat 49 – B 3000 Leuven, Belgium
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Study type:
Multicenter retro-and prospective observational cohort study

Hypothesis:
We hypothesize that the prevalence of Crohn Disease (CD)-related polymorphisms in intestinal transplant (ITx) donors and recipients increases the risk of allograft rejection and graft loss.

Aim:
Genotype retro- and prospectively ITx donors and recipients for CD-related mutations and study the effects on transplant outcomes (rejection, graft loss and survival).

Background:
Intestinal transplantation (ITx) remains challenging for several reasons, including the direct contact of the graft with a hostile bacterial environment. ITx is known for its high rate of rejection and poor long-term outcome. For this reason, ITx is mostly only advised in patients with life-threatening complications1–3.
Paneth cells (PC) in Crohn’s disease: PC shape the composition of the intestinal microbiota and maintain intestinal homeostasis by secreting defensins and mediating immune response4.  Damage of PC likely contributes to bacterial translocation, sepsis, ischemia-reperfusion injury and allograft rejection after ITx5,6. The importance of PC in intestinal homeostasis is highlighted by the effect of genetic mutations which affect PC cell function and lead toCrohn’s Disease (CD). Over 70 genetic risk loci have been identified, of which 3 major pathways in CD pathogenesis can be identified: microbial sensing (innate immunity), autophagy and Endoplasmatic Reticulum (ER) stress (Table 1).7,8

Pathway

Gene

SNP

Microbial sensing

NOD2

Rs2066844

 

 

Rs2066845

 

 

Rs2066847

Autophagy

ATG16L1

Rs2241880

 

IRGM

Rs100651172

 

 

Rs4958847

 

ULK1

Rs12303764

ER stress

XBP1

Rs35873774

 

ORMDL3

Rs2872507

Table: Genome-wide association studies have revealed 9 single nucleotide polymorphisms (SNP) associated to three different pathways that seem related to the pathogenesis of CD.

Fishbein et al. showed a correlation between NOD2 polymorphisms and intestinal allograft rejection9. Moreover, it was suggested that ITx recipients with NOD2 mutations had decreased PC defensin secretion. These findings suggest an unrecognized link between the recipient’s immune system, donor graft and allograft rejection.

Methods:
Collaboration with the KU Leuven IBD group led by Prof. Dr. Vermeire.

  • All ITx types included. Donors and/or recipients. Retro- and/or prospective.
  • Blood or tissue samples and basic data (demographics, survival, rejection episodes) collected and send by participating center
  • DNA genotyped for CD-related polymorphisms by KU Leuven

Ethical approval has been granted by the local Institutional Review Board.

Costs:
- DNA genotyping and analysis by KU Leuven
- Statistical analysis by KU Leuven
- Sample collection by participating center
- Transport by KU Leuven

Transport:
DNA (extraction at participating center) or whole blood send by DHL medical express under the packaging requirement of UN3373 (biological substance cat B, non-infectious) (http://www.dhl.be/en/express/industry_solutions.html#med). No other specific requirements requested.

Publication:
International peer-reviewed journal, 2 or 3 authors per center.

Bibliography:
1.        Fishbein, T. M. Intestinal transplantation. N. Engl. J. Med. 361, 998–1008 (2009).
2.        Abu-Elmagd, K. M. et al. Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann. Surg. 250, 567–581 (2009).
3.        Pironi, L. et al. Long-term follow-up of patients on home parenteral nutrition in Europe: implications for intestinal transplantation. Gut 60, 17–25 (2011).
4.        Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).
5.        Grootjans, J. et al. Human intestinal ischemia-reperfusion-induced inflammation characterized: experiences from a new translational model. Am. J. Pathol. 176, 2283–91 (2010).
6.        Grootjans, J. et al. Level of activation of the unfolded protein response correlates with Paneth cell apoptosis in human small intestine exposed to ischemia/reperfusion. Gastroenterology 140, 529–539.e3 (2011).
7.        Hoefkens, E. et al. Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress. Autophagy 9, 2046–2055 (2013).
8.        Fritz, T., Niederreiter, L., Adolph, T., Blumberg, R. S. & Kaser, A. Crohn’s disease: NOD2, autophagy and ER stress converge. Gut 60, 1580–8 (2011).
9.        Fishbein, T. et al. NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine. Gut 57, 323–330 (2008).