Faculty Bibliography

PURPOSE/UNASSIGNED:HLA sensitization significantly limits donor availability and increases waitlist mortality in pediatric heart transplantation (HT). Current desensitization strategies are largely ineffective or equivocal. Recent adult studies show that a dual approach with Carfilzomib (CFZ), a proteasome inhibitor, and Belatacept (BELA), a costimulation blocker, reduces class I and II HLA antibodies (Abs). This study will evaluate the clinical utility of CFZ and BELA in reducing HLA antibody type and strength in pediatric and young adult patients. METHODS/UNASSIGNED:This prospective, observational study will include about 30 patients from 6 pediatric clinical sites, an HLA core and a mechanistic core lab. Patients aged 10-24 years, highly sensitized with class I and/or class II cPRA ≥ 50% (MFI > 4000), will be included. Exclusion criteria: EBV seronegative, HIV+, and a history of hematologic malignancy. Secondary endpoints include mechanistic studies on how desensitization affects cellular subsets producing HLA Abs, whether reductions in antibody strength persist until transplant, and post-transplant outcomes such as antibody mediated rejection and graft survival. RESULTS/UNASSIGNED:The study's unique design harmonizes the use of a novel protocol across sites using a central IRB and is the first prospective, registry-based investigation in pediatric HT using the Pediatric Heart Transplant Society (PHTS) registry. The HLA core will measure antibody response through MFIs, titers, and cPRA, while the mechanistic core will use advanced investigations to support the trial's clinical endpoints. CONCLUSION/UNASSIGNED:This multicenter study aims to establish a transformative, standardized approach to desensitization and antibody evaluation.

The Sensitization in Transplantation: Assessment of Risk (STAR) initiative aims to translate HLA laboratory data into clinical practice and identify key knowledge gaps to guide future research. The STAR working group has held three consensus meetings and published reports that have influenced clinical care. In 2025, the group focused on five evolving areas: donor-derived cell-free DNA (dd-cfDNA) tests, innate immunity in allograft rejection, immunogenicity and antigenicity, HLA antibody quantification, and non-HLA antibodies. Three years of work culminated in two webinars and a February 2025 community meeting summarized in this report. The group outlined considerations for integrating dd-cfDNA tests into practice, proposed a definition for genetic prediction of NK-cell missing self, and discussed monocyte activation via the SIRPα-CD47 pathway. They reviewed molecular mismatch approaches, limitations, and immune-recognition complexities. Finally, they provided updates on HLA antibody quantification, non-HLA antibodies, and ongoing studies addressing critical knowledge gaps.

BACKGROUND:Under the HOPE Act, transplants from donors with HIV to recipients with HIV (HIV D+/R+) have been largely limited to kidney and liver. However, recent modifications to HOPE research guidelines allow broader participation of cardiothoracic programs. METHODS:To quantify potential cardiothoracic HOPE donors, we used SRTR data (3/2016-12/2024) to identify 101,200 donors without HIV and 273 HOPE donors (with true and false positive HIV tests). Using logistic regression, we predicted the probability of having a heart or lung(s) used for transplant among donors without HIV that had a kidney or liver used. We then applied model parameters to HOPE donors that had a kidney or liver used to estimate the number of HOPE donors that might have been cardiothoracic donors if the practice were expanded. RESULTS:Among donors without HIV, cardiothoracic donation was associated with age, cause of death, hepatitis C, hypertension, diabetes, smoking, cardiovascular disease, blood gas, and circulatory death. Applying our model, an estimated 41.0% (N=111), 18.7% (N=51), and 15.2% (N=41) of HOPE donors were potential heart, any lung (single or double), or double-lung donors, as compared to 32.3%, 21.8%, and 18.2% of abdominal organ donors without HIV, respectively. This translated to an annual 13-18 potential heart and 5-8 potential lung transplants (of which 4-6 would be double-lung transplants) from HOPE donors. CONCLUSIONS:If HIV D+/R+ is more widely expanded to cardiothoracic transplantation, 41% of HOPE kidney and liver donors have potential to donate a heart and almost 20% to donate a lung to candidates with HIV.

Allosensitization remains a major barrier in thoracic organ transplantation, limiting access to transplantation and increasing waitlist mortality and post-transplant morbidity. Desensitization protocols aimed at improving access to transplantation and mitigating the risk of early post-transplant rejection have been developed, but current strategies have limited efficacy, and new strategies are needed. After a synthetic description of the basics of alloimmune responses leading to the production of donor-specific antibodies, the potential of novel desensitization strategies, including anti-CD38 therapies, costimulation blockade, and interleukin-6 inhibition as pretransplant desensitization therapies, are discussed in detail, including the rationale for their use, results of preclinical and clinical studies, and potential practical clinical application. Complementary novel pharmacologic (individualization therapies, combination desensitization therapies, additional perioperative antibody-risk mitigation strategies) and nonpharmacologic strategies (individual risk stratification and combination of immunologic assays) are also presented. Finally, potential next-generation therapies (bispecific T-cell engager and chimeric antigen receptor T cells) and clinical outcomes of interest are briefly discussed. Overall, this review aims to provide recent data on this constantly evolving field, while keeping in mind the clinical applicability and providing practical aspects of the use of novel pretransplant desensitization therapies.

Developing real-world evidence from electronic health records (EHR) is vital to advance kidney transplantation (KT). We assessed the feasibility of studying KT using the Epic Cosmos aggregated EHR dataset, which includes 274 million unique individuals cared for in 238 U.S. health systems, by comparing it with the Scientific Registry of Transplant Recipients (SRTR). We identified 69,418 KT recipients transplanted between January 2014 and December 2022 in Cosmos (39.4% of all US KT transplants during this period). Demographics and clinical characteristics of recipients captured in Cosmos were consistent with the overall SRTR cohort. Survival estimates were generally comparable, although there were some differences in long-term survival. At 7 years post-transplant, patient survival was 80.4% in Cosmos and 77.8% in SRTR. Multivariable Cox regression showed consistent associations between clinical factors and mortality in both cohorts, with minor discrepancies in the associations between death and both age and race. In summary, Cosmos provides a reliable platform for KT research, allowing EHR-level clinical granularity not available with either the transplant registry or healthcare claims. Consequently, Cosmos will enable novel analyses to improve our understanding of KT management on a national scale.

Indirect CD4⁺ T cell allorecognition of donor peptides presented by host MHC class II antigens contributes to transplant rejection in part by eliciting donor-specific antibodies (DSAs). In this issue of Immunity, Zhanzak et al. revisit the role of indirectly alloreactive CD4⁺ T cells in transplantation and demonstrate that immunodominant epitopes stimulate a narrow repertoire of T cells that can be pruned to prevent DSA formation.

While advances in immunosuppression management have led to excellent 1-year survival after heart transplantation, long-term outcomes remain suboptimal. Contemporary therapies are associated with adverse sequalae, dominated by chronic kidney disease, and concomitantly by the inadequate control of humoral alloimmunity that is tightly linked to cardiac allograft vasculopathy. The dichotomy between the need for less toxicity and better control of humoral alloimmunity has driven a search for more effective regimens and for strategies to reverse humoral responses. This review provides an overview of immunosuppression in heart transplantation, beginning with critical historical context and followed by basic immunological principles underlying contemporary immunosuppression, the evolution of therapies over the past decade, and considerations for strategies to mitigate humoral alloimmunity. Perspective on the state-of-the field in the current era and considerations for future directions are also provided.

BACKGROUND:An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression. METHODS:Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated. RESULTS:<0.001). CONCLUSIONS:Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.

Left ventricular assist devices (LVADs) are associated with the development of antihuman leukocyte antigen (HLA) antibodies, which can create a challenge for future transplantation in these patients. The differential effects of Heartmate 3 (HM3) versus Heartmate II (HMII) on de novo HLA allosensitization remain unknown. Patients who underwent HMII or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing were included in this study. Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels and Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Electronic medical records were reviewed to examine posttransplant outcomes. Thirty-eight HM3 and 34 HMII patients with complete data were followed for 1.5 ± 1.1 years on device support. HM3 and HMII groups had similar age at implant, female gender, ischemic heart failure etiology, bridge strategy at implant, as well as intraoperative and postoperative transfusion requirements. 39.5% of HM3 and 47.1% of HMII patients developed detectable HLA antibodies by Luminex testing (p = 0.516). Development of high-level (mean fluorescence intensity >10,000) antibodies was significantly lower in HM3 than HMII patients (5.3 vs. 20.6%, p = 0.049). CDC PRA testing showed fewer HM3 patients with a positive result (PRA > 0%) than HMII patients (39.4 vs. 70.0%, p = 0.015). Among transplanted patients, those who had developed de novo sensitization on LVAD support showed a trend toward incidence of moderate to severe grade rejection compared with unsensitized patients (23.8 vs. 4.8%, p = 0.078). HM3 is associated with lower risk of de novo HLA sensitization compared with HMII.

Unlike immunocompetent hosts, the duration of viral persistence after infection with severe acute respiratory syndrome coronavirus 2 can be prolonged in immunosuppressed patients. Here, we present a case of viral persistence for over 19 weeks in a patient with a history of solid organ transplant and explore the clinical, virologic, and immunologic course. Our patient still demonstrated viral persistence at 138 days with low polymerase chain reaction cycle threshold values and evidence of continuing viral sequence evolution indicative of ongoing virus replication. These findings have important implications for infection prevention and control recommendations in immunosuppressed patients. Immune response, including neutralizing antibody titers, T cell activity, and cytokine levels, peaked around days 44-72 after diagnosis. Anti-S trimer antibodies were low at all time points, and T cell response was attenuated by day 119. As immune response waned and viral load increased, increased genetic diversity emerged, suggesting a mechanism for the development of viral variants.