Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 202 references
Medicine
TL;DR
The treatment paradigm is transitioning from empirical combination therapy to biomarker−driven, multi−target precision intervention covering the entire sequence of “production–circulation–effector pathways”, and the rationale underlying this evolution is delineated.
Abstract
Antibody-mediated rejection (AMR) is the primary immunological obstacle limiting long-term survival in heart transplant recipients. Driven by donor-specific antibodies (DSA), AMR damages graft microvasculature through multiple pathways, including complement activation, antibody-dependent cellular cytotoxicity, and sustained endothelial activation. It may present as acute hemodynamic collapse or progress insidiously in a subclinical manner, ultimately culminating in cardiac allograft vasculopathy (CAV) and graft failure. Over the past two decades, with successive updates to the ISHLT pathological diagnostic system, AMR has evolved from a vague clinical concept into a distinct entity defined by explicit histopathological and immunopathological criteria. However, therapeutic advances have markedly lagged behind the deepening understanding of its diagnosis. For a long time, the first−line regimen has consisted of plasma exchange combined with intravenous immunoglobulin (IVIG). Nevertheless, its mechanism—clearance of circulating antibodies plus broad−spectrum immunomodulation—neither targets the source of antibody production (long−lived plasma cells) nor selectively blocks terminal effector pathways. Approximately 30–50% of refractory AMR cases respond poorly to this regimen. Over the past decade, agents targeting plasma cells (proteasome inhibitor bortezomib), the terminal complement component (C5 monoclonal antibody eculizumab), the IL−6 pathway (tocilizumab, clazakizumab), and the more recent anti−CD38 monoclonal antibody (daratumumab) have entered clinical practice, shifting AMR treatment from having no actionable targets to enabling multi−node intervention. This review delineates the rationale underlying this evolution: the treatment paradigm is transitioning from empirical combination therapy to biomarker−driven, multi−target precision intervention covering the entire sequence of “production–circulation–effector pathways.” However, the field remains in a distinct transitional phase characterized by “weapons available but tactics lacking”—the vast majority of evidence derives from single−center, retrospective, small−sample observational studies, with no randomized controlled trial (RCT) specifically designed for AMR in heart transplantation. Consensus is lacking on how to select, combine, and sequence these agents based on individual immune phenotypes. Stratified therapy, dynamic biomarker monitoring, and rational multi−target combination will be the core directions for solving this challenge in the coming decade.
ABSTRACT Background Antibody-mediated rejection (ABMR) is a major cause of chronic allograft dysfunction and graft loss after kidney transplantation (KTx). Daratumumab, antibody targeting the transmembrane glycoprotein CD38 (cluster of differentiation) on immune cells, has shown promise in the treatment of refractory ABMR in adult solid organ transplantation; however, pediatric data are scarce. Methods We report two pediatric cases of refractory ABMR after KTx treated with daratumumab with followed-up protocol biopsies over 10–12 months. Treatment consisted of an induction phase with five weekly doses followed by maintenance dosing every two to four weeks. Donor-specific antibodies (DSAs), kidney function, albuminuria, and histologic response were assessed. Results The first case, a 10-year-old girl with recurrent ABMR after KTx showed histologic improvement from active ABMR with C4d positivity, glomerulitis, and severe microvascular inflammation to predominantly chronic changes without signs of active rejection. Microvascular inflammation became mild and C4d staining turned negative. The second case, a 9-year-old boy with active and chronic antiglomerular basement membrane disease and severe transplant ABMR glomerulopathy initially showed progression of chronic injury, followed by complete histologic resolution of active disease, disappearance of C4d staining, minimal fibrosis (<1%), and marked reduction of albuminuria after 10 months. Both patients demonstrated reduced DSA levels, stabilization of graft function, and no serious adverse events. Conclusion Daratumumab was associated with histologic improvement, reduction of microvascular inflammation, and stabilization of graft function in two children with refractory ABMR after KTx. Controlled studies to determine the safety, efficacy, and optimal dosage of daratumumab in children with ABMR are needed.
N. Kanzelmeyer, M. Verboom, M. Hallensleben et al.· Clinical Kidney Journal· 0 citations
BACKGROUND
Antibody-mediated rejection (AMR), driven by donor-specific antibodies (DSAs), remains a major cause of kidney allograft dysfunction. Conventional therapies reduce circulating antibodies and target precursor B cells but often fail to eliminate long-lived plasma cells, contributing to persistent or recurrent DSAs. CD38 is highly expressed on antibody-secreting cells, making it a selective therapeutic target for plasma cell depletion. Daratumumab, a fully human anti-CD38 IgG1κ monoclonal antibody, mediates depletion of CD38-expressing cells.
OBJECTIVES
Summarize the mechanistic rationale of daratumumab, review published experience with daratumumab in kidney transplantation, and describe a single-center experience using daratumumab for early, refractory AMR.
METHODS
We conducted a narrative review of CD38 targeting in AMR and evaluated a retrospective single-center case series of kidney transplant recipients (KTRs) treated with daratumumab after suboptimal response to institutional first-line therapy. Kidney allograft biopsy findings, DSA trajectories, and renal function parameters were trended during follow-up. This study complied with the Declaration of Helsinki and the Declaration of Istanbul; no organs were procured from prisoners or paid donors.
RESULTS
Two highly sensitized KTRs developed early acute AMR with persistent DSAs despite first-line therapies. Repeat biopsies demonstrated chronic active AMR (Patient 1) and ongoing/smoldering AMR (Patient 2). Subcutaneous daratumumab was initiated in both patients and there was a durable reduction in DSAs and stabilization or improvement in allograft function.
CONCLUSIONS
Daratumumab may serve as an adjunctive option for refractory AMR with persistent DSAs by targeting plasma cell-mediated alloantibody production. Prospective studies are required to define optimal dosing, timing, safety monitoring, and patient selection.
S. Sridhara, Elizabeth L Cho, J. Nelson et al.· Transplantation Proceedings· 0 citations
One of the leading causes of long-term graft loss following kidney transplantation is antibody-mediated rejection (AMR). In this process, donor-specific antibodies (DSAs), arising either from pre-transplant sensitization or developing de novo after transplantation, induce injury to the graft endothelium. This triggers microvascular inflammation, which may eventually progress to transplant glomerulopathy and graft dysfunction. In recent years, HLA eplet mismatch analysis has provided a more refined approach for predicting de novo DSA development, leading to a more precise assessment of immunogenetic risk in clinical practice. Despite these advances, polyclonal regulatory T cell (Treg) therapies have shown limited efficacy, largely due to their lack of antigen specificity. In contrast, CAR-Treg cells directed against intact donor HLA molecules or other defined alloantigenic targets offer a more targeted strategy. In this framework, HLA eplet mismatch analysis is best interpreted as a high-resolution tool for immunogenetic risk stratification and therapeutic matching rather than as a direct template for eplet-specific CAR construction. These cells engage in complex, localized modulation of Tfh-B cell interactions via cytokine-mediated pathways rather than simple Tfh suppression, thereby limiting germinal center reactions and effectively reducing DSA production. This review examines the immunopathogenesis of AMR, eplet-based risk assessment, the role of the follicular immune network, and the clinical potential of CAR-Treg therapy in light of current evidence. Taken together, by integrating high-resolution immunogenetic stratification with recent insights into the follicular immune network, this review clarifies how CAR-Treg therapies may be positioned within personalized tolerance strategies in transplantation.
N. Ekinci, Habibe Sema Arslan Unal· Human Immunology· 0 citations
Antibody-mediated rejection (AMR) is a serious post–lung transplant (LTx) complication with a challenging diagnosis. Histopathological findings associated with AMR include variable degrees of capillary inflammation, endotheliitis, and diffuse alveolar damage/organizing pneumonia. AMR has been historically related to anti-HLA donor-specific antibodies (DSA), while the role of non-HLA antibodies remains debated. We report the case of a 15-year-old male undergoing bilateral LTx for cystic fibrosis. Twenty days later, the patient developed moderate acute cellular rejection (ACR); in samples not affected by ACR, diffuse edema, capillary inflammation, and high p-S6RP expression scores were observed in macrophages, endothelial and epithelial cells. Anti-HLA class II DSA [maximum median fluorescence intensity (MFI): 10434] supported a diagnosis of mixed cellular/humoral rejection. After steroid therapy, DSA markedly decreased (maximum MFI: 1534), and ACR resolved, whereas persistent capillary inflammation and high p-S6RP expression in all cell types characterized sequential biopsies, raising suspicion for ongoing subclinical AMR. The persistence of these morphological features, together with sustained p-S6RP overexpression, prompted extended immunological testing, which revealed markedly elevated antibodies against endothelin type A receptor and angiotensin II type 1 receptor (>40 U/mL) in the patient follow-up. This case underscores the pivotal role of histopathological findings in multidisciplinary decision-making and highlights the importance of extended immunological screening. Our findings further support the emerging pathogenic relevance of non-HLA antibodies in the development and persistence of AMR in LTx recipients. The patient ultimately died 25 months after transplantation from progressive chronic lung allograft dysfunction.
F. Lunardi, M. Vadori, M. Loy et al.· Frontiers in Medicine· 0 citations
BACKGROUND
Late graft survival after pediatric heart transplantation (HT) remains inadequate, with chronic rejection being a major contributor. Daratumumab has shown promise treating antibody-mediated rejection (ABMR) with limited published experience in HT.
METHODS
We retrospectively analyzed all HT recipients at our center treated with daratumumab (16 mg/kg × 4 doses) for ABMR identified by elevated donor-derived cell-free DNA (dd-cfDNA) without graft dysfunction or hemodynamic compromise and confirmed by endomyocardial biopsy gene expression profiling (EMB-GEP). HLA-DSA and non-HLA antibodies, including angiotensin II type 1 receptor (AT1R) antibody, were assessed pre- and post-treatment.
RESULTS
Ten recipients were identified and treated with daratumumab, including 4 without HLA-DSA at diagnosis. dd-cfDNA decreased (1.6% to 0.04%; p=0.002) post-treatment. Among 8 with post-treatment EMB, ABMR resolved (n=6) or showed only possible ABMR (n=2) after treatment. HLA-DSA total MFI (p=0.031), non-HLA antibody burden (p=0.004), and AT1R Ab concentration (p=0.004) declined post-treatment. Six patients experienced subsequent elevations of dd-cfDNA at a median of 246 days (IQR, 239-283) with ABMR recurrence on EMB and responded to retreatment. No T-cell mediated rejection occurred after treatment.
CONCLUSIONS
Daratumumab was associated with significant improvements in dd-cfDNA, EMB-GEP, and antibody burden in pediatric and young adult HT recipients with ABMR. Response among patients without circulating HLA-DSA or with reduced but persistent HLA-DSA after treatment implies effects beyond plasma cell depletion. Rebound ABMR was common but responded to retreatment, suggesting periodic maintenance dosing may be required. Prospective studies are needed to define optimal treatment strategies and long-term outcomes.
Yuen Lo Yau Leung, Qingyong Xu, M. Zinn et al.· The Journal of Heart and Lun...· 1 citation
Long-term immunosuppressant use after solid organ transplantation causes serious complications, including chronic rejection, infection, malignancy, and metabolic disorders, which has motivated the clinical pursuit of immune tolerance induction. Sequential antibody induction protocols – using peri-transplant antibodies (e.g., alemtuzumab, anti-thymocyte globulin, belatacept, anti-CD40 monoclonal antibodies) combined with phased reduction or withdrawal of maintenance drugs – aim to establish “operational tolerance” or complete tolerance. This review systematically examines the immunological rationale and major clinical strategies (T-cell depletion, costimulation blockade, mixed chimerism, and regulatory cell therapy). Based on efficacy, safety, and feasibility, we propose four novel sequential regimens with explicit evidence levels. Our multidimensional feasibility assessment – covering cost, complexity, risk–benefit, patient selection, and regulatory barriers – indicates that costimulation-blockade protocols currently offer the best balance for near-term clinical use, whereas chimerism approaches are the most effective but remain restricted to specialised centres. Future work should integrate precise immune stratification, advanced antibody engineering, and cell-based therapies to facilitate individualized sequential protocols, ultimately moving the field from lifelong immunosuppression to controlled immune tolerance.
Yachao Li, Fu-Xia Chen, Xia He et al.· Frontiers in Immunology· 0 citations
