Chirurgie, Fysiologie En Immunologie Verbinden Om De Complexiteit Van Darmtransplantatie Te Ontrafelen

Intestinal transplantation (ITx) and multivisceral transplantation (MvTx) remain life-saving options for patients with intestinal or abdominal failure when other treatments have been exhausted, but their broader use is limited by a challenging postoperative course driven primarily by infection and rejection. This thesis examines the surgical, physiological, and immunological determinants of ITx/MvTx outcomes through both clinical and experimental approaches. At the clinical level, we first investigated living donation (LD) as a strategy to address donor scarcity and improve donor-recipient matching. Although the anticipated benefits of better HLA matching did not translate into improved outcomes, likely due to poorer pre-transplant clinical status in LD recipients, LD was shown to be feasible and safe, including in pediatric and highly sensitized patients. We then explored the genetic determinants of transplant outcome in an international cohort of 150 ITx recipients, identifying IBD-related variants in donors and recipients associated with rejection risk, with worse outcomes when variants were shared by both. Pathway analysis revealed that donor variants were linked to epithelial function and innate immunity, while recipient variants involved both innate and adaptive responses, underscoring the central role of the intestinal barrier in donor-recipient interactions. Finally, we assessed residual beta-cell function in recipients with differing pancreatic mass, showing that retaining more than one pancreas was associated with higher beta-cell function, supporting graft pancreas inclusion when technically feasible. At the experimental level, we evaluated strategies to mitigate ischemia-reperfusion injury (IRI). Alpha1-antitrypsin pretreatment markedly improved survival in a rat model of intestinal ischemia, likely through inhibition of neutrophil activity, supporting its translational potential given its established clinical safety profile. A systematic review further identified ferroptosis inhibition as a promising therapeutic target across solid organ transplantation, with several inhibitors showing efficacy in intestinal ischemia models. We also developed a structured learning framework for the rat ITx model, defining the procedural milestones required to achieve technical proficiency, and characterized long-term graft permeability changes following transplantation, revealing increased paracellular permeability despite preserved transcellular function, suggesting persistent structural consequences of denervation and lymphatic disruption. Together, these findings advance understanding of the surgical, physiological, and immunological factors shaping ITx/MvTx outcomes and identify several actionable targets—including donor-recipient genetic matching, graft pancreas inclusion, and IRI modulation—that may help improve outcomes and broaden the clinical applicability of intestinal and multivisceral transplantation