The role of immune cells settled in the bone marrow on adult hematopoietic stem cells.

Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis.

Ruxolitinib for steroid-refractory chronic graft-versus-host disease: Japanese subgroup analysis of REACH3 study.

Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population.

[Induction and regulation of intestinal graft-versus-host disease by the intestinal microbiota].

The intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HCT), and decreased diversity of the intestinal microbiota is linked to shorter overall survival, high transplant-related mortality, and acute graft-versus-host disease (GVHD). Major factors that alter the intestinal microbiota during allo-HCT are broad-spectrum antibiotics and intestinal GVHD. Broad-spectrum antibiotics dysregulate the immune system and impair intestinal epithelial regeneration by reducing beneficial commensal bacteria and activating mucus-degrading bacteria, which disrupts the colonic barrier function. Intestinal GVHD leads to decreased secretion of antimicrobial peptides into the intestinal lumen, as well as mitochondrial dysfunction in the intestinal epithelium, altering the intestinal microbiota. Various therapeutic approaches targeting the intestinal microbiota have been investigated in clinical trials. Protecting the intestinal microbiota may further enhance the safety and efficacy of allo-HCT by regulating intestinal immune responses, promoting intestinal epithelial regeneration, and facilitating the production of beneficial metabolites derived from commensal bacteria.

Clinical Manifestations and Outcomes of Ocular Graft Versus Host Disease following Allogeneic Stem Cell Transplantation.

Purpose: To evaluate clinical presentation of chronic ocular graft-versus-host disease (GVHD), laterality of presentation, and longitudinal changes in patients undergoing allogeneic stem cell transplantation. Methods: This is a retrospective longitudinal analysis of 60 eyes from 30 patients who had undergone hematopoietic stem cell transplantation. Demographic characteristics, clinical history, comorbidities, and other organ involvements were taken into account for analysis. We also undertook complete evaluation of the eyes, including cornea and anterior segment, posterior segment, Schirmer test, tear break-up time, ocular surface disease index, and intraocular pressure. Results: The mean age of the patients was 34.3 ± 11 years. The mean time for the diagnosis of ocular GVHD was 232.8 days (95% CI: 153.6, 311.9). The common findings at the first visit were bilateral blepharitis (n = 5, 17%), meibomitis (n = 4, 13%), and conjunctival congestion (n = 3, 10%). While bilateral cataract was present in one (3%) patient at the first visit, at 18 months, five (17%) patients had bilateral cataract and one (3%) patient had unilateral cataract. Grade 1 (n = 17), grade 2 (n = 9), and grade 3 (n = 4) superficial punctate epithelial erosions (SPEEs) were also observed at the first visit. However, SPEEs were seen in only 11 eyes at 18 months; all of these cases were grade 1 SPEEs. Long-term findings included cataract, telangiectasia, blepharospasm, conjunctival congestion, grade 1 SPEEs, corneal filaments, and tear film debris. Conclusion: Although the initial presentations were SPEEs, meibomitis, blepharitis, and conjunctival congestion, these inflammatory conditions were reduced over time with proper management. However, there was an increase in the proportion of patients with cataract. It is important to regularly monitor these patients in order to identify and manage the initial as well as the late ocular manifestations of chronic GVHD.

A Biobehavioral Perspective on Caring for Allogeneic Hematopoietic Stem Cell Transplant Survivors with Graft-Versus-Host Disease.

Among the potential complications of allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) is common and associated with significant physical and psychosocial symptom burden. Despite substantial advances in GVHD treatment, the global immune suppression that frequently accompanies GVHD treatment also contributes to high rates of physical and emotional suffering and mortality. The complex manifestations of GVHD and its treatment warrant a multidisciplinary team-based approach to managing patients' multi-organ system comorbidities. A biobehavioral framework can enhance our understanding of the complex association between medications, physical symptoms, and psychosocial distress in patients with GVHD. Hence, for this perspective, we highlight the importance of addressing both the physical and psychosocial needs experienced by patients with GVHD and provide guidance on how to approach and manage those symptoms and concerns as part of comprehensive cancer care.

Cutaneous Chronic Graft-Versus-Host Disease: Clinical Manifestations, Diagnosis, Management, and Supportive Care.

Cutaneous chronic graft-versus-host disease (cGVHD) is associated with morbidity, mortality, and impaired quality of life after hematopoietic stem cell transplantation. The clinical features of cutaneous cGVHD are heterogeneous but can be broadly classified into nonsclerotic or sclerotic presentations. This review provides an overview of clinical presentation, diagnosis and differential diagnosis, grading, and treatment of cutaneous cGVHD. Particular attention is given to cutaneous cGVHD in skin of color, which can have unique features and is generally underrepresented in the literature leading to delays in diagnosis. Finally, an overview of long-term skin care for patients with cutaneous cGVHD is provided in order to support patients from a dermatologic perspective as they recover from cGVHD. Multidisciplinary care with frequent communication between transplant specialists and dermatologists is critical to effectively managing cutaneous cGVHD.

Chronic Ocular GVHD Treatment at Two Locations of a Tertiary Referral Center.

Purpose: To compare baseline characteristics and treatment of chronic ocular graft-versus-host disease (oGVHD) patients in two treatment locations. Patients and Methods: Patients diagnosed with definite chronic oGVHD between September 1, 2014 and September 20, 2021 at two locations were identified. IRB-approved retrospective chart review was conducted for the following data: demographic information, ocular surface disease index (OSDI), corneal fluorescein staining (CFS), and treatment(s) used. Differences by site were assessed using Pearson's Chi-Square tests and two-sample t-tests; differences by time were assessed using paired t-tests. Results: At baseline, Clinic 1 (C1) patients had a worse mean OSDI score (47.8 vs 36.3, p = 0.011) and CFS in both OD (1.3 vs 0.8, p = 0.005) and OS (1.3 vs 0.6, p < 0.001) compared to Clinic 2 (C2). Comparing baseline to endpoint, C1 patients experienced an improvement in OSDI (-17.26, p < 0.001), CFS OD (-0.50, p < 0.001), and CFS OS (-0.51, p < 0.001) at C1. Change in OSDI, CFS OD, or CFS OS was not statistically significant at C2. Despite similar follow-up length, C1 demonstrated more clinic visits (10.4 vs 3.4, p < 0.001) and more treatment trials (4.9 vs 2.4, p < 0.001) compared to C2. Punctal plugs (85.5% vs 61.2%, p = 0.002), punctal cautery (69.7% vs 28.6%, p < 0.001), topical steroids (72.4% vs 22.4%, p < 0.001), and autologous serum tears (AST) (52.6% vs 8.2%, p < 0.001) were used more frequently at C1 than at C2. Conclusion: oGVHD patients at C1 experienced significant improvement in OSDI and corneal fluorescein staining and compared to patients at C2, had more frequent follow-up and use of punctal plugs, punctal cautery, topical steroids, and AST.

Biobehavioral mechanisms underlying symptoms in cancer patients with chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and high symptom burden. This study evaluated two biobehavioral mechanisms, inflammation and circadian rest-activity rhythms, that may underly commonly reported psychological and physical symptoms in cGVHD patients. Adults with cGVHD (N=57) wore a wrist actigraph for 7 days, provided a blood sample, and completed patient-reported outcome (PRO) measures. 24-hour rest-activity indices were derived from actigraphy. Cytokines and chemokines relevant to cGVHD were measured in peripheral blood plasma using multi-analyte immunoassays. Multiple regression evaluated the extent to which rest-activity indices and inflammatory biomarkers predicted PROs. Higher levels of circulating IL-8 and MIP-1α were associated with worse depression (ß = 0.35, p = 0.01; ß = 0.33, p = 0.02) and sexual function (ß = -0.41, p = 0.01; ß = -0.32, p = 0.03). MIP-1α was associated with more severe insomnia (ß = 0.36, p = 0.01). Higher circulating MIF was associated with more severe anxiety (ß = 0.28, p = 0.048) and fatigue (ß = 0.35, p = 0.02). Il-6, TNFα, and MCP-1 showed few associations with PROs. There were few associations between actigraphy indices and PROs; however, participants with a later daily activity peak (acrophase) reported poorer sexual function (ß = -0.31, p = 0.04). Models covarying for age, cGVHD severity, and time since HCT yielded a similar pattern of results. Results suggest that pro-inflammatory cytokines and chemokines associated with cGVHD may contribute to PROs, identifying a biobehavioral mechanism that may be a useful target for future interventions.

The prophylactic application of low-dose rabbit antithymocyte globulin in matched siblings HSCT with high-risk factors for graft-versus-host disease.

Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

Fatal graft-versus-host disease in recipient with pretransplant exposure to immune checkpoint inhibitors and donor-dominant one-way HLA matching after liver transplantation: A case report.

INTRODUCTION AND IMPORTANCE: Graft-versus-host disease (GvHD) is a rare but severe complication following liver transplantation (LT), occurring in 1-2 % of cases with a mortality rate exceeding 80 %. Immune checkpoint inhibitors (ICIs) used pretransplant are associated with increased allograft rejection risk, but their impact on GvHD in LT remains unclear. Dominant one-way donor-recipient human leukocyte antigen (HLA) matching is a known risk factor for GvHD. This report presents a rare case of fatal GvHD in a hepatocellular carcinoma (HCC) patient treated with PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching. CASE PRESENTATION: A 59-year-old male with a 30-year history of hepatitis B and unresectable HCC underwent LT after receiving the last dose of PD-1 inhibitors 7 days prior to the transplant. On post-operative day (POD) 12, the patient developed a skin rash, fever, and vomiting, and was diagnosed with GvHD. Despite aggressive treatment, including high-dose corticosteroids and extracorporeal membrane oxygenation (ECMO), the patient succumbed to gastrointestinal bleeding and multi-organ failure on POD 30. HLA genotyping revealed typical donor-dominant one-way HLA matching. CLINICAL DISCUSSION: This case highlights a potential link between pretransplant exposure to ICIs and GvHD, particularly with donor-dominant one-way HLA matching. Residual anti-PD-1 antibodies may activate graft-resident immune cells, precipitating GvHD. Further research with larger cohorts and animal models is required to clarify this relationship and understand the underlying mechanisms. CONCLUSION: Besides allograft rejection, caution should also be exercised regarding GvHD in patients with prior exposure to ICIs before LT.

Acute lymphoblastic leukemia with pneumatosis cystoides intestinalis after hematopoietic stem cell transplantation: a case report.

Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by air accumulation within the subserosa or submucosa of the gastrointestinal wall. We herein report a case involving a woman in her early 30s who developed PCI after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. The patient had a history of multiple COVID-19 infections. Imaging revealed extensive pneumoperitoneum and mesenteric emphysema; nevertheless, the patient remained clinically stable with a benign abdominal examination. She eventually recovered after 1 month of conservative treatment. We believe the PCI in this case had a multifactorial etiology, potentially involving both HSCT and COVID-19. Raising awareness of PCI may help avoid unnecessary surgical interventions and associated morbidity.

[Recto-colic graft-versus-host disease (GVH). Diagnostic and prognostic criteria in a cohort of patients from Amiens university hospital]. / Maladie du greffon contre l'hôte (GVH) recto-colique. Critères diagnostiques et pronostiques sur une cohorte de patients du CHU d'Amiens.

INTRODUCTION: Recto-colic graft-versus-host disease (GVHD) is a frequent and serious complication of hematopoietic stem cell allogeneic transplantation, which is sometimes difficult to diagnose. The aim of our study was to identify histological diagnostic and prognostic criteria for recto-colic GVH. MATERIAL AND METHOD: Patients allografted at Amiens university hospital from 2012 to 2017 were retrieved. Those who had a recto-colic biopsy were included and divided into two groups (final diagnosis of GVH and non-GVH), then biopsies were reviewed by 2 pathologists. RESULTS: One hundred and nineteen patients were included. Sixty-seven were allocated to the GVH group and 52 to the non-GVH group. In the GVH group, we observed a significantly greater number of apoptotic bodies (AB) on standard HES staining and with the anti-Caspase 3 immunohistochemistry, cryptolytic AB abscesses, atrophy, regenerative glands and glands lined with eosinophilic cells (P<0.001). Anti-Caspase 3 immunohistochemistry revealed more AB than standard HES staining (P<0.005). But to differentiate GVH cases from non-GVH cases, we obtained a threshold value of 3.5 AB per 10 contiguous crypts on standard HE staining and with the anti-Caspase 3 immunohistochemistry. From 4 AB per 10 contiguous crypts, on HES staining and anti-Caspase 3 immunostaining, the diagnosis of GVH became consistent. No non-GVH case had more than 6 AB per 10 contiguous crypts. GVH patients with more than 8 AB per 10 contiguous crypts had a worse prognosis (P<0.001). CONCLUSION: We confirm the value of AB and their counting in the diagnosis of GVH, with a diagnostic threshold of 4 AB and a prognostic threshold of 8 AB. Glands lined with eosinophilic cells could be an additional diagnostic criterion in favor of GVH to be confirmed by further studies.

Perspective on oral medication adherence among patients with acute graft-versus-host disease: a qualitative descriptive study.

PURPOSE: Despite the importance of adherence to immunosuppressants (IMMs) after an allogeneic haematopoietic stem cell transplant (HSCT) for the treatment of acute graft-versus-host disease (aGvHD), no studies to date have reported the experiences of such patients concerning medication adherence (MA). Therefore, the aim of the study was to explore the perspective on MA to immunosuppressive oral therapy among allogeneic HSCT patients with aGvHD. METHODS: A qualitative descriptive study following a reflexive thematic analysis methodological approach was performed involving a purposive sample of 16 patients with aGvHD who were being cared for in the outpatient setting of a bone marrow transplant centre and were willing to participate. Semi-structured audio-recorded interviews were conducted, transcribed verbatim and thematically analysed; member checking was performed. COnsolidated criteria for REporting Qualitative research (COREQ) and the ESPACOMP Medication Adherence Reporting Guideline were followed. RESULTS: Participants aged 25-74 years and mostly males (62.5%) were recruited for this study; 56.2% developed grade I, 37.5% grade II and 6.3% grade III aGvHD; 56.2% were receiving treatment with both cyclosporine and prednisone. Patients' perspectives have been summarised into four themes, named: "Transiting from an external obligation to a habit"; "Being in the middle between the negative and positive effects of the IMMs"; "Failure to systematically respect the rules"; and "Adopting personal strategies to become adherent". After difficulties with the perception of feeling obliged, patients became used to adhering to IMMs. Although there were failures in systematically taking the medication correctly and there were episodes of non-adherence, the adoption of personal strategies helped patients to become adherent to their medication schedules. CONCLUSIONS: MA in patients with aGvHD is a complex behaviour and is often a challenge. These results can help healthcare professionals and centres to understand how best to design tailored strategies and behavioural interventions to maximise patients' MA to IMMs.

Effects and Safety of 5% Lifitegrast Ophthalmic Solution in Patients With Dry Eye Disease Associated With Ocular Graft-Versus-Host Disease.

Introduction Graft-versus-host disease (GVHD) is a common sequela of hematopoietic stem cell transplant (HSCT). While HSCT is often curative for certain hematologic malignancies, acute and chronic GVHD remains an important cause of morbidity and mortality in post-transplant patients. Ocular involvement is one manifestation of chronic GVHD that can present similarly to chronic dry eye with tear film abnormalities, aqueous deficiency, and corneal epithelial defects through melting and perforation. Current management includes frequent use of artificial tears and oral or topical glucocorticoids as tolerated. There is a need for long-term, steroid-sparing therapeutics in the management of ocular GVHD (oGVHD). Lifitegrast is approved for the treatment of chronic dry eye and may have therapeutic potential in the treatment of oGVHD. The aim of this study was to investigate the efficacy and safety of topical lifitegrast in the management of oGVHD. Methodology A prospective randomized clinical trial (NCT04792580) was performed on 32 enrolled patients with diagnosed oGVHD. Subjects underwent a two-week washout period consisting of preservative-free artificial tears dosed twice a day, after which they were randomized to the treatment arm (5% lifitegrast ophthalmic solution) or placebo arm (vehicle solution) for four weeks. Endpoints included Symptom Assessment iN Dry Eye (SANDE) score, unanesthetized Schirmer score, Ocular Surface Disease Index questionnaire score, fluorescein staining, tear film breakup time, meibum quantity, and turbidity. Safety endpoints included intraocular pressure, visual acuity, and rate of treatment-related adverse effects. Statistical analysis was done with a t-test or Wilcoxon rank-sum test. Results The primary and secondary efficacy endpoints were met, with statistically significant reductions in mean SANDE and unanesthetized Schirmer score observed at four weeks post-randomization. No serious adverse events related to the use of either lifitegrast or vehicle were observed, and no worsening of visual acuity or intraocular pressure occurred in the intention-to-treat analysis. However, further inference was limited due to insufficient statistical power owing to significant washout and a 50% dropout rate from the all-enrolled analysis set. The most common causes of study dropout were worsening of unrelated medical conditions (not GVHD) and improvement of SANDE score or Schirmer score outside of the inclusion criteria range during the washout period. Conclusions Lifitegrast may be a useful steroid-sparing agent in the long-term management of oGVHD. This study provides further support for the clinical evidence of lifitegrast in the management of dry eye signs and symptoms, although further sufficiently powered clinical trials are warranted to better understand its efficacy in the oGVHD population. Personalized treatment options targeting distinct manifestations of oGVHD in the cornea, tear film, lid margin, and conjunctiva are needed in the effective management of this multifaceted and complex disease.

Identification of predictive models including polymorphisms in cytokines genes and clinical variables associated with post-transplant complications after identical HLA-allogeneic stem cell transplantation.

Backgrounds: Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies, it can be associated with relevant post-transplant complications. Several reports have shown that polymorphisms in immune system genes are correlated with the development of post-transplant complications. Within this context, this work focuses on identifying novel polymorphisms in cytokine genes and developing predictive models to anticipate the risk of developing graft-versus-host disease (GVHD), transplantation-related mortality (TRM), relapse and overall survival (OS). Methods: Our group developed a 132-cytokine gene panel which was tested in 90 patients who underwent an HLA-identical sibling-donor allo-HSCT. Bayesian logistic regression (BLR) models were used to select the most relevant variables. Based on the cut-off points selected for each model, patients were classified as being at high or low-risk for each of the post-transplant complications (aGVHD II-IV, aGVHD III-IV, cGVHD, mod-sev cGVHD, TRM, relapse and OS). Results: A total of 737 polymorphisms were selected from the custom panel genes. Of these, 41 polymorphisms were included in the predictive models in 30 cytokine genes were selected (17 interleukins and 13 chemokines). Of these polymorphisms, 5 (12.2%) were located in coding regions, and 36 (87.8%) in non-coding regions. All models had a statistical significance of p<0.0001. Conclusion: Overall, genomic polymorphisms in cytokine genes make it possible to anticipate the development all complications studied following allo-HSCT and, consequently, to optimize the clinical management of patients.

Vedolizumab for second-line treatment of steroid-refractory gastrointestinal late acute graft-versus-host disease.

Background: Late acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with little data regarding treatment and outcomes. There is no standard treatment for gastrointestinal (GI) late aGVHD, especially for steroid-refractory (SR) GI late aGVHD. Vedolizumab, a monoclonal antibody inhibiting the migration of both naive and activated lymphocytes into the GI endothelium, has been verified to be effective for SR GI aGVHD. Methods: We retrospectively analyzed the clinical efficacy and safety of vedolizumab as the second line for SR GI late aGVHD in seven patients after allo-HSCT. Results: Four patients received two doses of vedolizumab infusion, while three patients received only one dose of vedolizumab infusion. The complete response and partial response rates were 57.1% (4/7) and 42.9% (3/7), respectively. No patient progressed to chronic GVHD during the period of follow-up. There was no severe adverse event related to vedolizumab. Conclusion: Our data suggest that vedolizumab is expected to ameliorate SR GI late aGVHD. Further data on the treatment timing, efficacy, and safety of vedolizumab are warranted in prospective clinical trials.

Role of liver biopsy in the management of idiosyncratic DILI.

Drug-induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft-versus-host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation.

Allogeneic amnion transplantation for the management of cutaneous graft-versus-host disease with associated ulcers: A promising therapeutic strategy.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is the cornerstone treatment for various hematopoietic disorders, but its utility is often compromised by chronic graft-versus-host disease (cGvHD), affecting skin integrity and leading to ulcer formations. Traditional treatments, including systemic and topical therapies, frequently fail in severe cases. This study retrospectively examines three patients with therapy-resistant ulcers due to cGvHD post-alloSCT treated at the University Hospital of Regensburg in 2023. We evaluated the therapeutic impact of human amniotic membrane (hAM) transplantation-a novel approach utilizing hAM's anti-inflammatory, anti-microbial, and anti-fibrotic properties for wound healing. Surgical debridement was followed by hAM application and routine follow-up. HAM transplantation led to complete wound closure in two out of three patients and a significant reduction in local pain and infection rates. The treatment alleviated the need for regular dressing changes within three months in two patients, demonstrating the hAM's efficacy in fostering rapid and sustained healing. The utilization of hAM represents a promising alternative for the management of refractory skin ulcers in cGvHD patients, particularly when conventional methods are inadequate.

Immune isolation-enabled nanoencapsulation of donor T cells: a promising strategy for mitigating GVHD and treating AML in preclinical models.

BACKGROUND: In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking. METHODS: In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways. RESULTS: Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells. CONCLUSIONS: Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.