Total pancreatectomy with islet autotransplantation (TPIAT) is a reliable therapy to retain endocrine function, to alleviate pain and improve quality of life in adult and pediatric patients suffering from refractory chronic pancreatitis and recurrent acute pancreatitis. Recently, an expansion of indications to include benign and malignant pancreatic disease has been suggested. Improved methods for evaluating the functional quality of islets and predicting transplant outcome have been discussed. Furthermore, this review will discuss the recent advances in the procedure, anti-inflammatory strategies and outcomes of TPIAT. New assays to measure posttransplant islet damage and improved methods to assess islet quality by monitoring the oxygen consumption rate have shown great promise. Anti-inflammatory strategies such as an interleukin-1 receptor antagonist, α-1 antitrypsin, tumor necrosis factor α inhibitor and an inhibitor of CXCR1/2 have been widely investigated under clinical trials. The primary objective of TPIAT, which is to relieve pain and reduce narcotic usage, has been shown to have long-term success. However, achieving long-term insulin independence is still a challenge that needs to be addressed. The mechanism that leads to chronic graft failure in TPIAT needs to be delineated.

Islet culture before clinical transplantation has been adopted by various centers, but its effect on the survival and function of islets relative to the culture conditions and media needs further assessment. Human islets were cultured or preserved under four different conditions and three media options. Parameters such as recovery, viability, function, islet damage, and gene expressions for markers of hypoxia, and inflammation were assessed after 48-h culture or preservation. Preservation of islets was performed at 4°C in Connaught’s Medical Research Lab (CMRL) and University of Wisconsin (UW) media. Islets were cultured at 22°C, 37°C, and 37°C–22°C in CMRL and PRODO culture media. Islets preserved in UW solution had visually good morphology and exhibited higher recovery with less islet damage compared with the rest of the groups, whereas islets preserved in CMRL at 4°C resulted in poor morphology, recovery, viability, and function compared with the rest of the treatment conditions. Culture at 22°C and 37°C demonstrated an increase in the expression of inflammatory and hypoxia-related genes. In conclusion, islets preserved at 4°C in UW solution showed the best overall outcomes after 48 h compared with islets cultured at 22°C, 37°C, or 37°C–22°C in PRODO. Advancement in islet culture media is warranted to reduce inflammatory gene activation and improve recovery of islets for transplantation.

Islets experience enormous stress during the isolation process, leading to suboptimal endocrine function after total pancreatectomy with islet autotransplantation (TPIAT). Our investigation focused on inducing isolation stress in islets ex vivo, where proinflammatory cytokines and hypoxia prompted the release of stress exosomes (exo^S) sized between 50-200nm. Mass spectrometry analysis revealed three distinct subgroups of immunogenic proteins within these exo^S: damage-associated molecular patterns (DAMPs), chaperones, and autoantigens. The involvement of endosomal sorting complex required for transport (ESCRT) proteins - RAB7A, RABGGTA, VPS45, VPS26B, and the tetraspanins CD9 and CD63 - in exo^S biogenesis was confirmed through immuno-blotting. Next, we isolated similar exo^S from the islet infusion bags of TPIAT recipients (N=20). The exosomes from infusion bags exhibited higher DAMP (HSPA1B, and histone H2B) levels, particularly in the insulin-dependent (ID) TPIAT group. Additionally, elevated DAMP protein levels in islet infusion bag exosomes correlated with increased insulin requirements (p=0.010) and higher HbA1c levels one year post-transplant. A deeper exploration into exo^S functionality revealed their potential to activate monocytes via the toll-like receptor TLR3/7: DAMP axis. This stimulation resulted in the induction of inflammatory phenotypes marked by increased levels of CD68, CD80, iNOS, and COX-2. This activation mechanism may impact the successful engraftment of transplanted islets.

In this letter, we provide data for the first time on the comparison of two cannulation methods used in human islet isolation: single cannula method (SCM) vs. dual cannula method (DCM). Islet Transplantation is an effective treatment for patients with refractory chronic pancreatitis (CP) and Type 1 Diabetes (T1D). Sufficient islets is required for achieving manageable metabolic status after transplantation. Collagenase infusion through the pancreatic duct is critical, as improper distention leads to poor yield (1).