Islet Transplant Recipients Research Articles

α- or β-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or β-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor β-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

337.8: Cost savings using the BETA-2 versus beta score in follow-up of islet transplant recipients in the UK islet transplant consortium

337.8: Cost savings using the BETA-2 versus beta score in follow-up of islet transplant recipients in the UK islet transplant consortium

Validation of Igls Criteria for Islet Transplant Functional Status Using Person-Reported Outcome Measures in a Cross-Sectional Study.

Associations between islet graft function and well-being in islet transplant recipients requiring exogenous insulin remain unclear. This cross-sectional analysis compared person-reported outcome measures in 15 adults with type 1 diabetes whose islet transplants were classified according to Igls criteria as "Good" (n = 5), "Marginal" (n = 4) and "Failed" (n = 6) graft function. At a mean of 6.2years post-first islet transplant, 90% reduction in severe hypoglycaemia was maintained in all groups, with HbA1c (mean ± SD mmol/mol) 49 ± 4 in recipients with "Good" function; 56 ± 5 ("Marginal"); and 69 ± 25 ("Failed"). Self-reported impaired awareness of hypoglycaemia persisted in all groups but those with "Good" function were more likely to experience symptoms during hypoglycaemia. "Marginal" function was associated with greater fear of hypoglycaemia (HFS-II score: "Marginal": 113 [95, 119]; "Failed": 63 [42, 93] (p = 0.082); "Good": 33 [29, 61]) and severe anxiety (GAD7: "Marginal"): 21 [17, 21]; "Failed": 6 [6, 6] "Good": 6 [3, 11]; (p = 0.079)), diabetes distress and low mood. Despite clear evidence of ongoing clinical benefit, Igls criteria 'Marginal' function is associated with sub-optimal well-being, including greater fear of hypoglycaemia and severe anxiety. This study provides person-reported validation that "Good" and "Marginal" graft function are differentiated by general and diabetes-specific subjective well-being, suggesting those with "Marginal" function may benefit from further intervention, including re-transplantation.

1498-P: Preemptive Insulin Supplementation for Islet Graft Protection, Optimal Blood Glucose Control, and Fetal Development during the Pregnancy in Insulin-Independent Patient after Islet Transplantation

Pregnancy increases metabolic demand for insulin, which may lead to the exhaustion of intraportally transplanted islets and postgestational hyperglycemia. Here we report a successful long-term preservation of islet graft function after two subsequent pregnancies while applying preemptive insulin supplementation. 29-year-old female with T1DM achieved long-term insulin independence with HbA1c &amp;lt;5.8% after a single intraportal islet transplant. Before conception, mycophenolate was replaced with azathioprine and tacrolimus target trough level was decreased to 4-6ng/ml. The patient became pregnant twice, 5 years and 7.5 years after her islet transplantation. During the first and second pregnancy patient preemptively supplemented with insulin up to 35-70u/day and up to 35 units daily, respectively to target fasting blood glucose below 90mg/ml. Postpartum the patient was successfully weaned off insulin maintaining optimal blood glucose control with HbA1c below 5.7%. Islet graft function before and after the pregnancy remained optimal as reflected by BETA-2 above 17 and comparable c-peptide secretion and peak blood glucose levels below 130mg/ml during the 8.5-year follow-up in Mixed Meal Tolerance Test. Both newborns were premature and delivered at 34 weeks with emergent c-sections due to preeclampsia. Unfortunately, the first newborn died due to necrotizing enterocolitis. The second child has been developing appropriately up-to-date three months after her birth. Our report confirms that insulin supplementation during pregnancy in insulin-independent patients after islet transplantation was safe and effective in maintaining optimal blood glucose control and islet graft function in the long term. It also underscores the high-risk nature of pregnancy in islet transplant recipients and the need for close clinical monitoring. Disclosure S.Gondek: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Diagnosis and treatment of allograft rejection in islet transplantation

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [−59.1% to −91.6%]; ΔC-peptide:glucose, −76.3% [−49.2% to −90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies.

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence.

Adjuvant conditioning induces an immunosuppressive milieu that delays alloislet rejection through the expansion of myeloid-derived suppressor cells

Advances in immunosuppression have been relatively stagnant over the past 2 decades, and transplant recipients continue to experience long-term morbidity associated with immunosuppression regimens. Strategies to reduce or eliminate the dosage of immunosuppression medications are needed. We discovered a novel administration strategy using the classic adjuvant alum to condition murine islet transplant recipients, known as adjuvant conditioning (AC), to expand both polymorphonuclear and monocytic myeloid-derived suppressive cells (MDSCs) in vivo. These AC MDSCs potently suppress T cell proliferation when cultured together in vitro. AC MDSCs also facilitate naïve CD4+ T cells to differentiate into regulatory T cells. In addition, we were able to demonstrate a significant delay in alloislet rejection compared with that by saline-treated control following adjuvant treatment in a MDSC-dependent manner. Furthermore, AC MDSCs produce significantly more interleukin (IL)-10 than saline-treated controls, which we demonstrated to be critical for the increased T cell suppressor function of AC MDSCs as well as the observed protective effect of AC against alloislet rejection. Our data suggest that adjuvant-related therapeutics designed to expand MDSCs could be a useful strategy to prevent transplant rejection and curb the use of toxic immunosuppressive regimens currently used in transplant patients.

Vaccine Effectiveness Against the SARS-CoV-2 B.1.1.529 Omicron Variant in Solid Organ and Islet Transplant Recipients in England: A National Retrospective Cohort Study.

The effectiveness of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 Omicron variant in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear. National registries in England were linked to identify SARS-CoV-2 positive tests, noninjury hospitalization within 14 d, and deaths within 28 d between December 7, 2020, and March 31, 2022 in adult SOT recipients. Incidence rate ratios (IRRs) for infection, and hospitalization or death, were adjusted for recipient demographics and calendar month for the Omicron-dominant period (December 20, 2021, to March 31, 2022). Mortality risk following SARS-CoV-2 infection was adjusted for recipient demographics and dominant variant using a Cox proportional-hazards model for the entire time period. During the Omicron-dominant period, infection IRRs (95% confidence intervals) were higher in those receiving 2, 3, and 4 vaccine doses than in unvaccinated patients (1.25 [1.08-1.45], 1.46 [1.28-1.67], and 1.79 [1.54-2.06], respectively). However, hospitalization or death IRRs during this period were lower in those receiving 3 or 4 vaccine doses than in unvaccinated patients (0.62 [0.45-0.86] and 0.39 [0.26-0.58], respectively). Risk-adjusted analyses for deaths after SARS-CoV-2 infection between December 7, 2020, and March 31, 2022, found hazard ratios (95% confidence intervals) of 0.67 (0.46-0.98), 0.46 (0.30-0.69), and 0.18 (0.09-0.35) for those with 2, 3, and 4 vaccine doses, respectively, when compared with the unvaccinated group. In immunosuppressed SOT recipients, vaccination is associated with incremental, dose-dependent protection against hospitalization or death after SARS-CoV-2 infection, including against the Omicron variant.

P16.02: Safety and Effectiveness of COVID-19 Vaccination in the Islet Transplant Recipients

Background: Response to Covid vaccine among transplant recipients remains diminished comparing to general population. Here, we assessed safety and effectiveness of the Covid vaccination in the protection from the Covid infection and in the induction of the SARS-CV-2 Spike total antibody (Spike ab) in islet transplant recipients. Methods: We analyzed immune response to Covid-19 and COVID-19 vaccination in a cohort of 20 islet transplant recipients: N=13 after islet transplant alone (ITx), N=7 with islet after kidney (IAK) or pancreas after islet graft (PAI). The median age was 48 years (25-62). Maintenance immunosuppression included tacrolimus and an antimetabolite in addition to 5mg of Prednisone in IAK and PAI recipients. Four patients got booster. Results: Seven patients (38%) chose not to be vaccinated and 5 (71%) of them remained Covid-19 free with no Spike ab present in their blood. The other two patients (29%) had only mild symptoms of COVID-19 infection with Spike ab detected afterwards (46U/ml -IAK and 180U/ml- ITx). In contrast, all remaining 13 patients (62%), who received vaccination: N= 8 Pfizer, N=4 Moderna, N=1 J&J while on immunosuppression for a median of 7 years (0.5-16), remained Covid-19 free based on lack of symptoms and PCR testing (p=0.11, Fischer). The level of Spike ab in response to vaccine varied: undetected- (N=4), range- 5-40U/ml (N=4), range around 75U/ml (N=2), around 400U/ml (N=2), and above 2,500U/ml (N=1). Presence of 5mg of Prednisone did not affect the outcomes. None of the patients experienced moderate/serious adverse events related to the vaccination. Booster administered 4-6 months after the second dose of the vaccine increased the level of Spike ab from 22, 92, 441 to over 2,500 in all 3 patients, respectively. One patient who did not developed any Spike ab after Pfizer vaccine, also did not respond to the booster. Islet graft function remained stable in all patients during 8-12 months after initial vaccination. There were no SAEs related to the vaccination or booster. Conclusion: One third of unvaccinated islet transplant recipients developed Covid-19, however, all of them presented only with mild symptoms. In contrast, none of vaccinated transplant patients developed COVID-19 infection with 69% rate of seroconversion after vaccination. Booster increased level of the Spike ab in those patients who responded to the original vaccination.

111-OR: Response to COVID-Vaccination and Infection in Islet Transplant Recipients

Background: Since response to COVID-vaccine among transplant recipients remains diminished comparing to general population, we decided to assess effect of COVID-specifically among islet transplant patients. Methods: Response to COVID-infection and vaccine was assessed in a cohort of 20 islet transplant recipients: N=13 after islet transplant alone (ITx) , N=7 with islet after kidney (IAK) or pancreas after islet transplantation (PAI) . The median age was 48 years (25-62) . Maintenance immunosuppression included tacrolimus and an antimetabolite in addition to 5mg of Prednisone in IAK and PAI recipients. Nine patients received booster. Results: Seven patients (38%) chose not to be vaccinated and 4 (57%) of them remained COVID-free with no SARS-CV-2 Spike total antibody (Spike ab) present in their blood. The other three patients (43%) developed only mild symptoms of infection with a high level of Spike ab (&amp;gt;2,500 U/ml) afterwards. In contrast, all remaining 13 patients (62%) , who were vaccinated while on immunosuppression for a median of 7 years (0.5-16) , remained COVID-free (p=0.11, Fischer) . The level of Spike ab in response to vaccine varied: undetected- (N=4) , in range 1-100U/ml (N=6) , around 400U/ml (N=2) , and above 2,500U/ml (N=1) . Presence of 5mg of Prednisone did not affect the outcomes. Booster was administered in patients and increased the level of Spike ab above 100U/ml in all of them, in 7 (78%) to over 2,500 U/ml. One patient responded neither to vaccine nor to booster. There were no SAEs related to the vaccination or booster. Islet graft function remained stable in all but one patient after initial vaccination or COVID-19. Conclusion: Nearly half of unvaccinated islet transplant recipients developed Covid-19, however, all of them presented only with mild symptoms. In contrast, none of vaccinated transplant patients developed COVID-infection with 69% rate of seroconversion. Booster increased level of the Spike ab in those patients who responded to the original vaccination. Disclosure B.Juengel: None. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. P.J.Bachul: None. A.Perez-gutierrez: None. L.Basto: None. L.Perea: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: n/a. Funding NIDDK P30 DK020595

Real-world Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients.

Background.The clinical effectiveness of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear.Methods.We linked 4 national registries to retrospectively identify laboratory-confirmed SARS-CoV-2 infections and deaths within 28 d in England between September 1, 2020, and August 31, 2021, comparing unvaccinated adult SOT recipients and those who had received 2 doses of ChAdOx1-S or BNT162b2 vaccine. Infection incidence rate ratios were adjusted for recipient demographics and calendar month using a negative binomial regression model, with 95% confidence intervals. Case fatality rate ratios were adjusted using a Cox proportional hazards model to generate hazard ratio (95% confidence interval).Results.On August 31, 2021, it was found that 3080 (7.1%) were unvaccinated, 1141 (2.6%) had 1 vaccine dose, and 39 260 (90.3%) had 2 vaccine doses. There were 4147 SARS-CoV-2 infections and 407 deaths (unadjusted case fatality rate 9.8%). The risk-adjusted infection incidence rate ratio was 1.29 (1.03-1.61), implying that vaccination was not associated with reduction in risk of testing positive for SARS-CoV-2 RNA. Overall, the hazard ratio for death within 28 d of SARS-CoV-2 infection was 0.80 (0.63-1.00), a 20% reduction in risk of death in vaccinated patients (P = 0.05). Two doses of ChAdOx1-S were associated with a significantly reduced risk of death (hazard ratio, 0.69; 0.52-0.92), whereas vaccination with BNT162b2 was not (0.97; 0.71-1.31).Conclusions.Vaccination of SOT recipients confers some protection against SARS-CoV-2–related mortality, but this protection is inferior to that achieved in the general population. SOT recipients require additional protective measures, including further vaccine doses, antiviral drugs, and nonpharmaceutical interventions.

Simple Vaccination Is not Enough for the Transplant Recipient.

Simple Vaccination Is not Enough for the Transplant Recipient.

The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C‐peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C‐peptide at 12 months (p < .01). Despite 1.9‐fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C‐peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta −0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Considerations and challenges of islet transplantation and future therapies on the horizon.

Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.

105.4: Impact of the COVID-19 Lockdown on Behavior, Stress, Anxiety and Glycemic Control in Patients With Beta Cell Transplantation

Introduction: Patients with severely complicated type 1 diabetes (T1D) who receive β-cell transplantation (Tx) have multiple risk factors for a severe course of coronavirus disease, including the use of immunosuppression (IS). Lockdown strategies implemented due to the COVID-19 pandemic are known to impact both mental and physical health, but this impact is expected to be even greater in patients at high risk for a severe course of COVID-19. We therefore aimed to investigate the behavioral, mental and physical implications of the nationwide lockdown in islet and pancreas transplant recipients (referred to in this abstract as β-cell Tx). Methods: In order to study the effect of the lockdown on glycemic control, all patients with T1D and an islet transplantation or pancreas transplantation with non-optimal graft function according to the Igls criteria using IS were eligible. As a control group, patients with T1D without IS were included. Lockdown behavior and self-reported changes in anxiety, stress, physical activity, weight, and glycemic control were assessed using questionnaires. HbA1c and continuous glucose monitoring (CGM) metrics during lockdown were compared to measurements before lockdown. Results: Islet and pancreas (β-cell) Tx recipients (n = 51, age 55 (48 – 59) years, BMI 23.3 (20.9 – 27.4) kg/m2, diabetes duration 42 (34 – 48) years) adhered more stringently to lockdown measures compared to patients with T1D alone (n = 272, age 53 (37 – 62) years, BMI 25.2 (23.0 – 28.0) kg/m2, diabetes duration 27 (15 – 39) years). In β-cell Tx recipients as compared to T1D, 52.1% vs 18.3% (p <0.001) reported not going out for groceries and 45.8% vs 14.0% (p <0.001) reported not leaving the house at all. Fear of coronavirus infection was higher in β-cell Tx recipients (VAS 5.0 (3.0 – 7.0) vs 3.0 (2.0 – 5.0), p=0.004) and glycemic control worsened during lockdown as assessed by HbA1c (ΔHbA1c +1.67 ± 8.74 vs -1.72 ± 6.15 mmol/mol, p=0.006) as well as CGM (Δ time in range β-cell Tx -4.5% (-6.0% – 1.5%) vs T1D 3.0% (-2.0% – 6.0%), p=0.038; Δ time above range β-cell Tx 5.5% (-0.5% – 7.5%) vs T1D -3.0% (-7.5% – 3.0%), p=0.025). Among β-cell Tx recipients, 29.2% self-reported more difficulty with glycemic control, 26.8% increased insulin use, 40.0% less physical activity, 41.7% weight gain, 29.2% increased anxiety and 33.3% increased stress since the start of lockdown. Having had a β-cell Tx was the most important predictor of not leaving the house during the COVID-19 lockdown. Conclusions: The COVID-19 pandemic and subsequent lockdown add additional fear of infection, deterioration of glycemic control and more stringent social isolation behavior when patients with T1D also have an islet or pancreas transplant. These patients undertake less physical activity and experience more weight gain, stress and anxiety. Health care professionals should be aware of these behavioral, mental and physical implications to be able to provide extra support.

Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7days in the peri-transplant period.Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5±12.2years, 69% female), n=50 reparixin-treated, n=52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p=.542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p=.842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

Long-term Persistence of Allosensitization After Islet Allograft Failure.

Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.

Adapting Protocols or Models for Use in Insulin-Requiring Diabetes and Islet Transplant Recipients.

The authors’ perspective is described regarding modifications made in their clinic to glucose challenge protocols and mathematical models in order to estimate insulin secretion, insulin sensitivity and glucose effectiveness in patients living with Insulin-Requiring Diabetes and patients who received Pancreatic Islet Transplants to treat Type I diabetes (T1D) with Impaired Awareness of Hypoglycemia. The evolutions are described of protocols and models for use in T1D, and Insulin-Requiring Type 2 Diabetes (T2D) that were the basis for studies in the Islet Recipients. In each group, the need for modifications, and how the protocols and models were adapted is discussed. How the ongoing application of the adaptations is clarifying the Islet pathophysiology in the Islet Transplant Recipients is outlined.

Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus.

(1) Background: The correlation between titers of islet autoantibodies (IAbs) and the loss of transplanted islets remains controversial. We sought to evaluate the prognostic utility of monitoring IAbs in diabetic patients after islet transplantation (ITx); (2) Methods: Twelve patients with Type 1 diabetes mellitus and severe hypoglycemia underwent ITx. Serum concentration of glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), and zinc transport 8 (ZnT8) autoantibodies was assessed before ITx and 0, 7, and 75 days and every 3 months post-operatively; (3) Results: IA-2A (IA-2 antibody) and ZnT8A (ZnT8 antibody) levels were not detectable before or after ITx in all patients (median follow-up of 53 months (range 24–61)). Prior to ITx, GAD antibody (GADA) was undetectable in 67% (8/12) of patients. Of those, 75% (6/8) converted to GADA+ after ITx. In 67% (4/6) of patients with GADA+ seroconversion, GADA level peaked within 3 months after ITx and subsequently declined. All patients with GADA+ seroconversion maintained long-term partial or complete islet function (insulin independence) after 1 or 2 ITx. There was no correlation between the presence of IAb-associated HLA haplotypes and the presence of IAbs before or after ITx; (4) Conclusions: There is no association between serum GADA trends and ITx outcomes. IA-2A and ZnT8A were not detectable in any of our patients before or after ITx.

Examination of the Igls Criteria for Defining Functional Outcomes of β-cell Replacement Therapy: IPITA Symposium Report.

The Igls criteria were developed to provide a consensus definition for outcomes of β-cell replacement therapy in the treatment of diabetes during a January 2017 workshop sponsored by the International Pancreas & Islet Transplant Association (IPITA) and the European Pancreas & Islet Transplant Association. In July 2019, a symposium at the 17th IPITA World Congress was held to examine the Igls criteria after 2 years in clinical practice, including validation against continuous glucose monitoring (CGM)-derived glucose targets, and to propose future refinements that would allow for comparison of outcomes with artificial pancreas system approaches. Utilization of the criteria in various clinical and research settings was illustrated by population as well as individual outcome data of 4 islet and/or pancreas transplant centers. Validation against CGM metrics was conducted in 55 islet transplant recipients followed-up to 10 years from a fifth center. The Igls criteria provided meaningful clinical assessment on an individual patient and treatment group level, allowing for comparison both within and between different β-cell replacement modalities. Important limitations include the need to account for changes in insulin requirements and C-peptide levels relative to baseline. In islet transplant recipients, CGM glucose time in range improved with each category of increasing β-cell graft function. Future Igls 2.0 criteria should consider absolute rather than relative levels of insulin use and C-peptide as qualifiers with treatment success based on glucose assessment using CGM metrics on par with assessment of glycated hemoglobin and severe hypoglycemia events.