Guilherme Costa

Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid‐derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33+CD11b+ lineage(CD3/CD56/CD19)−HLA‐DR−/low cells with 3 subsets, CD14−CD15− (e‐MDSCs), CD14+CD15− (M‐MDSCs), and CD14−CD15+ (PMN‐MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M‐MDSC numbers were maintained at a high level after 2 months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)‐6 levels and the glucocorticoid administration index. IL‐6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M‐MDSCs and e‐MDSCs expressed CCR1, ‐2, and ‐3; e‐MDSCs and PMN‐MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45+ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor‐reactive T cell–mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR.

Technical Innovation and Visceral Transplantation

The improvement in outcomes of intestinal and multivisceral transplantation during the past two decades is the result of several factors, including innovations in surgical techniques. As it has become more practical, visceral transplantation has been successfully performed in patients with different forms of irreversible gastrointestinal failure. Accordingly, different combinations of en bloc abdominal visceral organ transplants are being used more frequently. In this chapter, we describe the three main prototypes of visceral transplantation and discuss the most relevant technical modifications of both the donor and recipient procedures.

Management of Crohn's Disease in the New Era of Gut Rehabilitation and Intestinal Transplantation.

Abstract:Despite recent therapeutic advances, patients with Crohns disease (CD) continue to experience high recurrence with cumulative structural damage and ultimate loss of nutritional autonomy. With short bowel syndrome, strictures, and enteric fistulae being the underlying pathology, CD is the second common indication for home parenteral nutrition (HPN). With development of intestinal failure, nutritional management including HPN is required as a rescue therapy. Unfortunately, some patients do not escape the HPN-associated complications. Therefore, the concept of gut rehabilitation has evolved as part of the algorithmic management of these patients, with transplantation being the ultimate life-saving therapy. With type 2 intestinal failure, comprehensive rehabilitative measures including nutritional care, pharmacologic manipulation, autologous reconstruction, and bowel lengthening is often successful, particularly in patients with quiescent disease. With type 3 intestinal failure, transplantation is the only life-saving treatment for patients with HPN failure and intractable disease. With CD being the second common indication for transplantation in adults, survival outcome continues to improve because of surgical innovation, novel immunosuppression, and better postoperative care. Despite being a rescue therapy, the procedure has achieved survival rates similar to other solid organs, and comparable to those who continue to receive HPN therapy. With similar technical, immunologic, and infectious complications, survival is similar in the CD and non-CD recipients. Full nutritional autonomy is achievable in most survivors with better quality of life and long-term cost-effectiveness. CD recurrence is rare with no impact on graft function. Further progress is anticipated with new insights into the pathogenesis of CD and mechanisms of transplant tolerance.

Imaging of Intestinal and Multivisceral Transplantation

Intestinal transplantation has evolved from its experimental origins in the mid-20th century to its status today as an established treatment option for patients with end-stage intestinal failure who cannot be sustained with total parenteral nutrition. The most common source of intestinal failure in both adults and children is short-bowel syndrome, but a host of other disease processes can lead to this common end-point. The development of intestinal transplantation has presented multiple hurdles for the transplant community, including technical challenges, immunologic pitfalls, and infectious complications. Despite these hurdles, the success rate has climbed over the past decades owing to achievements that include improved surgical techniques, new immunosuppressive regimens, and more effective strategies for posttransplant surveillance and management. Nearly 2800 intestinal transplants have been performed worldwide, and current patient and graft survival rates are now comparable to those of other types of solid organ transplantations. As their population continues to increase, it will be increasingly likely that intestinal-transplant patients will seek imaging at sites other than transplant centers. Therefore, it is important that diagnostic and interventional radiologists be familiar with the procedure, its common variations, and the spectrum of postoperative complications. In this article, the authors provide an overview of intestinal transplantation, including the indications, variations, expected postoperative anatomy, and range of potential complications. ©RSNA, 2018.

The Historic Evolution of Intestinal and Multivisceral Transplantation

This chapter focuses on the multifaceted historic evolution of visceral transplantation, with special reference to the pioneer experimental and clinical work triggered by the introduction of new premises, the availability of novel immunosuppressive drugs, and the innovation of surgical techniques. In addition, the current status of the different types of visceral transplantation is highlighted, with new insights for future consideration.

Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome

The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs.

Total pancreaticoduodenectomy with autologous islet transplantation 14 years after liver-contained composite visceral transplantation

Chronic pancreatitis (CP) is a severely disabling disorder with potential detrimental effects on quality of life, gut function, and glucose homeostasis. Disease progression often results in irreversible morphological and functional abnormalities with development of chronic pain, mechanical obstruction, and pancreatic insufficiency. Along with comprehensive medical management, the concept of total pancreatectomy and islet autotransplantation (TP‐AIT) was introduced 40 years ago for patients with intractable pain and preserved beta‐cell function. With anticipated technical difficulties, total excision of the inflamed‐disfigured gland is expected to alleviate the incapacitating visceral pain and correct other associated abdominal pathology. With retrieval of sufficient islet‐cell mass, the autologous transplant procedure has the potential to maintain an euglycemic state without exogenous insulin requirement. The reported herein case of CP‐induced recalcitrant pain and foregut obstruction is exceptional because of the technical challenges in performing native pancreaticoduodenectomy in close proximity to the composite visceral allograft with complex vascular and gut reconstructions. Equally novel is transplanting the auto‐islets in the liver‐contained visceral allograft. Despite intravenous nutrition shortly after birth, liver transplantation at age 13, retransplantation with liver‐contained visceral allograft at age 17 and TP‐AIT at age 31, the 38‐year‐old recipient is currently pain free with full nutritional autonomy and normal glucose homeostasis.

Surgery in Patients with Hepatic Cirrhosis: Management of Portal Hypertension

The inherent development of portal hypertension (PH) in patients with hepatic cirrhosis and portomesenteric venous thrombosis commonly influences the outcome of any required major surgical intervention. Accordingly, a thorough assessment is often required to define status of hepatic reserve, spectrum of PH, and complexity of the coexisted pathology. This includes comprehensive clinical, biochemical, endoscopic, radiologic, and histopathologic evaluation. In candidates with preserved synthetic liver functions, optimization of nutritional and global health status is imperative to reduce overall morbidity and mortality. With the diagnosis of gut varices and demonstration of portomesenteric abdominal collaterals, directed management strategy is required to avoid the potential risk of provoking life-threatening complications including variceal hemorrhage and surgical bleeding with subsequent development of hepatic failure. With the initial recognition of marginal hepatic reserve or subsequent development of liver failure, organ transplantation should be seriously considered. Accordingly, patients with portal hypertension who are in need for major surgical procedures should be managed at tertiary medical centers. The availability of a multidisciplinary team with expertise in the relevant fields improves the overall outcomes measures including survival and value of health care.