CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation.

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/TacTL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/TacTL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

High-resolution structure of native toxin A from Clostridioides difficile.

Clostridioides difficile infections have emerged as the leading cause of healthcare-associated infectious diarrhea. Disease symptoms are mainly caused by the virulence factors, TcdA and TcdB, which are large homologous multidomain proteins. Here, we report a 2.8 Å resolution cryo-EM structure of native TcdA, unveiling its conformation at neutral pH. The structure uncovers the dynamic movement of the CROPs domain which is induced in response to environmental acidification. Furthermore, the structure reveals detailed information about the interaction area between the CROPs domain and the tip of the delivery and receptor-binding domain, which likely serves to shield the C-terminal part of the hydrophobic pore-forming region from solvent exposure. Similarly, extensive interactions between the globular subdomain and the N-terminal part of the pore-forming region suggest that the globular subdomain shields the upper part of the pore-forming region from exposure to the surrounding solvent. Hence, the TcdA structure provides insights into the mechanism of preventing premature unfolding of the pore-forming region at neutral pH, as well as the pH-induced inter-domain dynamics.

Risk factors and outcomes of bloodstream infection from a urinary source in kidney transplant recipients.

BACKGROUND: Bacteriuria is common among kidney transplant recipients (KTR). Risk factors and outcomes associated with bloodstream infection due to a urinary source (BSIU) in KTR are poorly understood. METHODS: This single center case-control study from 2010 to 2022 compared KTR with BSIU to those with bacteria without bloodstream infection (BU). Multivariable logistic regression identified BSIU risk factors, and Cox models assessed its impact on graft failure. RESULTS: Among 3435 patients, who underwent kidney transplantation at Emory Hospital, 757 (22%) developed bacteriuria, among whom 142 (18.8%) were BSIU. Male sex, presence of Escherichia coli, Klebsiella pneumoniae, or Pseudomonas species in urine culture, urethral stricture, neuromuscular bladder disorder, and history of diabetes-induced renal failure were independently associated with increased odds of BSIU (Male sex: aOR 2.29, 95% CI 1.52, 3.47, E. coli: aOR 5.14, 95% CI 3.02, 9.13; K. pneumoniae aOR 3.19, 95% CI 1.65, 6.27, Pseudomonas spp aOR 3.06, 95% CI 1.25, 7.18; urethral stricture: 4.10, 95% CI 1.63, 10.3, neuromuscular bladder disorder aOR 1.98, 95% CI 1.09, 3.53, diabetes: aOR 1.64, 95% CI 1.08, 2.49). BSIU was associated with increased hazard of graft failure (HR 1.52, 95% CI 1.05, 2.20). CONCLUSION: Close monitoring is warranted for male KTR with bacteriuria, those with urine cultures positive for Pseudomonas spp, K. pneumoniae, or E. coli, as well as KTR with a history of diabetes-induced renal failure, urethral stricture, or neuromuscular bladder disorder due to their risk for developing BSIU. Future research should explore strategies to mitigate BSIU risk in these high-risk KTR and reduce the associated risk of long-term graft failure.

Impact of an ultrasensitive Cytomegalovirus quantitative nucleic acid test on Cytomegalovirus detection and therapy in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection has broad implications for morbidity and mortality in renal transplant recipients (RTR). Routine surveillance for CMV replication with PCR-based quantitative nucleic acid testing (qNAT) assays is standard practice in most transplant centers, but the impact of assay sensitivity on antiviral decision-making and virologic outcomes has not been studied. We investigated the effects of an ultrasensitive CMV qNAT assay on multiple clinical outcomes, including time to detection and duration of CMV DNAemia. METHODS: We conducted a single-center cohort study contrasting RTRs monitored with a qNAT with a higher lower limit of quantification (LLOQ >300 IU/mL) with those monitored with a more sensitive qNAT (LLOQ >35 IU/mL). Patients were stratified by donor (D)/recipient (R) CMV serostatus (D+/R-: high risk; any R+: moderate risk). CMV viral load monitoring was performed monthly post transplantation, with the primary outcomes being time to CMV DNAemia and its duration. RESULTS: Total 1382 patients were analyzed from 2014 to 2016 and 2019 to 2021. Moderate-risk RTRs monitored with the more sensitive assay experienced a greater hazard for the development of a first episode of CMV DNAemia (aHR: 1.95, 95% confidence interval [CI]: 1.55-2.46) and an average of 24 (95% CI: 16.40-31.98) additional days of DNAemia. There was no difference in CMV end-organ disease or 1-year all-cause mortality between moderate-risk RTRs. CONCLUSIONS: The more sensitive assay was associated with earlier detection and extended durations of CMV DNAemia in moderate-risk RTRs, without altering clinical outcomes. These findings inform optimal use of these assays and antiviral stewardship in RTRs. KEY SUMMARY: The use of ultrasensitive CMV qNAT assays in moderate-risk CMV renal transplant recipients is associated with earlier detection and longer durations of CMV DNAemia without impacting CMV end-organ disease or 1-year mortality.

Belatacept-based immunosuppression does not confer increased risk of BK polyomavirus-DNAemia relative to tacrolimus-based immunosuppression.

BACKGROUND: The effect of belatacept on BK polyomavirus (BKPyV) control remains largely unknown. METHODS: This is a propensity matched retrospective cohort study in adult kidney transplant recipients (KTR) transplanted between 2016-2020 who received a belatacept- versus tacrolimus-based immunosuppression regimen. A continuous time multi-state Markov model was used to evaluate BKPyV replication dynamics (BKPyV-dyn). Three BKPyV-dyn states were defined: BKPyV-dyn1 (viral load <3 log10), BKPyV-dyn2 (viral load ≥ 3 log10 and ≤4 log10), and BKPyV-dyn3 (viral load >4 log10). RESULTS: Two hundred eighty KTR on belatacept- and 280 KTR on tacrolimus-based regimens were compared. The probability of transitioning between BKPyV-dyn states and time spent in each state in both groups was comparable. Total duration in BKPyV-dyn-1 was 632.1 days (95% CI 612.1, 648.5) for belatacept versus 615.2 days (95% CI 592.5, 635.8) for tacrolimus, BKPyV-dyn-2 was 49.2 days (95% CI 41.3, 58.4) for belatacept versus 55.6 days (95% CI 46.5, 66.8) for tacrolimus, and BKPyV-dyn-3 was 48.7 days (95% CI 37.1, 363.1) for belatacept versus 59.2 days (95% CI 45.8, 73.5) for tacrolimus. BKPyV associated nephropathy (PyVAN) occurred in 3.9% in belatacept- and 3.9% tacrolimus-treated KRT (P > .9). CONCLUSIONS: Compared with tacrolimus-based immunosuppression, belatacept based immunosuppression was not associated with increased risk of BKPyV-DNAemia or nephropathy.

Detectable plasma severe acute respiratory syndrome coronavirus 2 spike antigen is associated with poor antibody response following third messenger RNA vaccination in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients (KTRs) generate lower antibody responses to messenger RNA (mRNA)-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, yet precise mechanisms for this poor response remain uncertain. One potential contributor is suboptimal spike antigen (sAg) translation and expression owing to transplant immunosuppression, which might lead to insufficient exposure to develop humoral and/or cellular immune responses. METHODS: Within a single-arm clinical trial, 65 KTRs underwent ultrasensitive plasma sAg testing before, and 3 and 14 days after, the third mRNA vaccine doses. Anti-SARS-CoV-2 spike antibodies (anti-receptor binding domain [anti-RBD]) were serially measured at 14 and 30 days post-vaccination. Associations between sAg detection and clinical factors were assessed. Day 30 anti-RBD titer was compared among those with versus without sAg expression using Wilcoxon rank sum testing. RESULTS: Overall, 16 (25%) KTRs were sAg positive (sAg+) after vaccination, peaking at day 3. Clinical and laboratory factors were broadly similar in sAg(+) versus sAg(-) KTRs. sAg(+) status was significantly negatively associated with day 30 anti-RBD response, with median (interquartile range) 10.8 (<0.4-338.3) U/mL if sAg(+) versus 709 (10.5-2309.5) U/mL if sAg(-) (i.e., 66-fold lower; p = .01). CONCLUSION: Inadequate plasma sAg does not likely drive poor antibody responses in KTRs, rather sAg detection implies insufficient immune response to rapidly clear vaccine antigen from blood. Other downstream mechanisms such as sAg trafficking and presentation should be explored.

Epitope Mapping of SARS-CoV-2 Spike Antibodies in Vaccinated Kidney Transplant Recipients Reveals Poor Spike Coverage Compared to Healthy Controls.

Kidney transplant recipients (KTRs) develop decreased antibody titers to SARS-CoV-2 vaccination compared to healthy controls (HCs), but whether KTRs generate antibodies against key epitopes associated with neutralization is unknown. Plasma from 78 KTRs from a clinical trial of third doses of SARS-CoV-2 vaccines and 12 HCs underwent phage display immunoprecipitation and sequencing (PhIP-Seq) to map antibody responses against SARS-CoV-2. KTRs had lower antibody reactivity to SARS-CoV-2 than HCs, but KTRs and HCs recognized similar epitopes associated with neutralization. Thus, epitope gaps in antibody breadth of KTRs are unlikely responsible for decreased efficacy of SARS-CoV-2 vaccines in this immunosuppressed population.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Comparison of convolutional neural networks for classification of vocal fold nodules from high-speed video images.

OBJECTIVES: Deep learning is in this study used through convolutional neural networks (CNN) to the determination of vocal fold nodules. Through high-speed video (HSV) images and computer-assisted tools, a comparison of convolutional neural network models and their accuracy will be presented. METHODS: The data have been collected by an Ear Nose Throat (ENT) specialist with a 90° rigid scope in the years from 2007 to 2019, where 15.732 high-speed videos have been collected from 7909 patients. A total of 4000 images have been carefully selected, 2000 images were of normal vocal folds and 2000 images were of vocal folds with varying degrees of vocal fold nodules. These images were then split into training-, validation-, and testing-data set, for use with a CNN model with 5 layers (CNN5) and compared to other models: VGG19, MobileNetV2, and Inception-ResNetV2. To compare the neural network models, the following evaluation metrics have been calculated: accuracy, sensitivity, specificity, precision, and negative predictive values. RESULTS: All the trained CNN models have shown high accuracy when applied to the test set. The accuracy is 97.75%, 83.5%, 91.5%, and 89.75%, for CNN5, VGG19, MobileNetV2, and InceptionResNetV2, respectively. CONCLUSIONS: Precision was identified as the most relevant performance metric for a study that focuses on the classification of vocal fold nodules. The highest performing model was MobilNetV2 with a precision of 97.7%. The average accuracy across all 4 neural networks was 90.63% showing that neural networks can be used for classifying vocal fold nodules in a clinical setting.

Aggregation-Induced Emission by Molecular Design: A Route to High-Performance Light-Emitting Electrochemical Cells.

The emission efficiency of organic semiconductors (OSCs) often suffers from aggregation caused quenching (ACQ). An elegant solution is aggregation-induced emission (AIE), which constitutes the design of the OSC so that its morphology inhibits quenching π-π interactions and non-radiative motional deactivation. The light-emitting electrochemical cell (LEC) can be sustainably fabricated, but its function depends on motion of bulky ions in proximity of the OSC. It is therefore questionable whether the AIE morphology can be retained during LEC operation. Here, we synthesize two structurally similar OSCs, which are distinguished by that 1 features ACQ while 2 delivers AIE. Interestingly, we find that the AIE-LEC significantly outperforms the ACQ-LEC. We rationalize our finding by showing that the AIE morphology remains intact during LEC operation, and that it can feature appropriately sized free-volume voids for facile ion transport and suppressed non-radiative excitonic deactivation.

Fecal Microbiota Transplantation Donor Screening Updates and Research Gaps for Solid Organ Transplant Recipients.

In this review, we discuss stool donor screening considerations to mitigate potential risks of pathogen transmission through fecal microbiota transplant (FMT) in solid organ transplant (SOT) recipients. SOT recipients have a higher risk for Clostridioides difficile infection (CDI) and are more likely to have severe CDI. FMT has been shown to be a valuable tool in the treatment of recurrent CDI (RCDI); however, guidelines for screening for opportunistic infections transmitted through FMT are underdeveloped. We review reported adverse effects of FMT as they pertain to an immunocompromised population and discuss the current understanding and recommendations for screening found in the literature while noting gaps in research. We conclude that while FMT is being performed in the SOT population, typically with positive results, there remain many unanswered questions which may have major safety implications and warrant further study.

Gluten-free diet reduces autoimmune diabetes mellitus in mice across multiple generations in a microbiota-independent manner.

Experimental and clinical data suggest that a gluten-free diet attenuates the development of type 1 diabetes. A gluten-free diet changes the gut microbiota composition, and such microbial changes are expected to reduce the autoimmune responses. However, in experiments with laboratory mice, a gluten-free diet changes the gut microbiota differently under varying experimental settings, questioning the specific role of the gut microbes. Here we show that a maternal gluten-free diet until weaning of their pups, delayed type 1 diabetes in both dams (parent generation) and offspring (F1 generation) of untreated non-obese diabetic (NOD) mice and in mice treated with a full cocktail of antibiotics that eradicates most of the existing microbiota. Breeding a second (F2) generation of NOD mice, never exposed to the gluten-free diet or the associated microbial changes, also demonstrated a preventative effect on type 1 diabetes even though their parents (the F1 generation) had only been on a gluten-free diet very early in life. Collectively, the experimental data, thus, points towards microbiota-independent dietary protection. Furthermore, both the perinatal gluten-free diet and antibiotic treatment reduced inflammation in the salivary glands and improved glucose challenged beta cell function in the F1 offspring. However, in contrast to the autoimmune response in the pancreas, those changes appeared to be microbiota dependent, as they were missing in the antibiotic treated mice, and do, therefore, not seem to be related to the preventative effect on type 1 diabetes. Interestingly, adoptive transfer of splenocytes from gluten-free fed mice protected NOD.SCID mice from developing diabetes, demonstrating that the anti-diabetic effect of a gluten-free diet was based on early life changes in the evolving immune system. In particular, genes involved in regulation of lymphocyte activation, proliferation, and cell adhesion were highly expressed in the spleen in gluten-free fed mice at weaning compared to control fed mice of the F1 generation, which suggested that gluten promotes autoimmunity by inhibiting immune regulation, though the involvement of the specific genes needs further investigation. In conclusion, gluten-free diet reduces autoimmune inflammation in salivary glands and pancreas in NOD mice in a microbiota-dependent and -independent manner respectively, and has preventative effect on type 1 diabetes by modulating the systemic immune system.

Temporal trends and current use of de novo belatacept in kidney transplant recipients in the United States.

The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo-belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept-based regimen with 3.03% using it in over 50% of their patients. The use of T-cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1-year post-transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long-term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.

Impact of belatacept and tacrolimus on cytomegalovirus viral load control and relapse in moderate and high-risk cytomegalovirus serostatus kidney transplant recipients.

BACKGROUND: Belatacept improves long-term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high-risk and moderate-risk recipients. METHODS: Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia. RESULTS: Among high-risk recipients, belatacept-treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus-treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High-risk belatacept-treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus-treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus-treated recipients (239 days, 95% CI = 195, 277). Moderate-risk recipients showed better viral load control and with no differences by immunosuppression. CONCLUSION: High-risk belatacept-treated recipients showed defects in sustaining viral control relative to tacrolimus-treated recipients. Avoidance of initial use belatacept in high-risk recipients or development of modified management protocols should be considered.

Biomarker-Based Assessment for Infectious Risk Before and After Heart Transplantation.

PURPOSE OF REVIEW: Survival outcomes for heart transplant recipients have improved in recent decades, but infection remains a significant cause of morbidity and mortality. In this review, we discuss several biological markers, or biomarkers, that may be used to monitor immunologic status in this patient population. RECENT FINDINGS: While modest, data on the utility of immune biomarkers in heart transplant recipients suggest correlation between low level of immune response and increased infection risk. More novel assays, such as the detection of circulating levels of pathogen cell-free DNA in plasma and the use of Torque teno virus load as a surrogate for net state of immunosuppression, have potential to be additional important biomarkers. Biomarker approaches to individualize immunosuppression therapy among heart transplant recipients is a promising area of medicine. However, additional studies are needed to inform the optimal protocol in which to incorporate these biomarkers into clinical practice.

CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept.

INTRODUCTION: Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals. METHODS: CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared. RESULTS: Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. CONCLUSION: Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients.

Kidney transplant recipients administered belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept-based maintenance regimens. Steroid-sparing, belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept-based regimen for minimizing early cellular AR occurrence.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c  ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.