Transplant immunology最新文献

Background: For CMV high-risk constellations, guidelines recommend 3-6 months of prophylaxis with valganciclovir (VGCV). Management in preventing CMV primary infection in patients developing VGCV-associated leukopenia remains challenging.

Methods: We retrospectively analyzed the development of leukopenia during VGCV prophylaxis in 57 seronegative kidney recipients of a CMV-seropositive donor between 2008 and 2021. We analyzed CMV risk and development of CMV-specific T cells in the first post-transplant year depending on leukopenia during VGCV prophylaxis and management with CMV-IVIg.

Results: Leukopenia developed in 19/57 patients, with a significant difference in leukocyte counts occurring after 10 weeks of VGCV prophylaxis compared to patients without leukopenia (p = 0.0003). VGCV discontinuation led to leukocyte reconstitution, which tended to be faster in patients receiving additional prophylaxis with CMV-IVIg after VGCV discontinuation (n = 11, p = 0.083). In the first post-transplant year, patients with leukopenia had no higher risk for severe CMV events. Interestingly, patients receiving CMV-IVIg prophylaxis showed a significantly lower peak CMV-load during primary infection (p = 0.040), with no difference in CMV-specific T-cell levels compared to patients without leukopenia or patients with additional CMV-IVIg prophylaxis (p = 0.972). Patients developing adequate CMV-specific T-cell responses less frequently underwent CMV reactivation 50 days following primary infection.

Conclusion: Leukopenia developed late during VGCV prophylaxis and did not result in an increased risk for CMV primary infections or severe disease. Leukopenic patients receiving CMV-IVIg tended to have a faster leukocyte reconstitution and had lower peak DNAemia, which did not adversely affect CMV-specific T-cell induction. CMV-IVIg may therefore be considered as an alternative prophylactic strategy in patients with VGCV-associated leukopenia.

Background: Sepsis-induced acute kidney injury (AKI) is a severe condition characterized by dysregulation of pro- and anti-inflammatory responses. Targeting macrophage polarization between pro-inflammatory M1 and anti-inflammatory M2 cells offers a potential therapeutic approach for AKI. Trametinib (TRAM), an inhibitor of the MEK1/2 signaling pathway, was evaluated for its impact on M1/M2 polarization in AKI.

Methods: Wild-type (WT) mice were subjected to lipopolysaccharide (LPS)-induced AKI and intraperitoneally treated with dimethyl sulfoxide (DMSO) or TRAM (10 mg/kg) for three days. Renal function was assessed by measuring creatinine levels. While histopathological changes, RNA sequencing data, and serum cytokine levels were analyzed. Macrophage M1/M2 polarization in kidney tissues was examined using flow cytometry and immunohistochemistry. Murine bone marrow-derived macrophages (BMDMs) were polarized to the M1 or M2 phenotype in vivo and treated with or without TRAM (10 μM). M1/M2 polarization was analyzed via flow cytometry, and PI3K/Akt signaling was evaluated by western blotting.

Results: TRAM significantly improved renal function, as demonstrated by reduced serum creatinine levels (p < 0.01) and ameliorated histopathological damage (p < 0.01). Flow cytometry and immunohistochemistry revealed that TRAM markedly inhibited pro-inflammatory M1 macrophage polarization (p < 0.001). Additionally, TRAM reduced serum level of IFN-γ (p < 0.01) and IL-17 (p < 0.001). In vitro, TRAM suppressed M1 polarization (p < 0.05) by inhibiting the PI3K/Akt signaling pathway.

Conclusion: TRAM mitigated LPS-induced AKI by suppressing M1 macrophage polarization via the PI3K/Akt pathway, highlighting its therapeutic potential for AKI and other inflammatory kidney diseases.

Background: The huge diversity of Human Leukocyte Antigen (HLA) system is well-known to be associated with various diseases, anthropology, population genetics, and transplantation. The frequencies of HLA alleles in different populations are crucial for both research and clinical applications. This study determined the allelic and haplotype frequencies of all HLA class I and class II loci in 595 consecutive samples from patients who underwent solid organ transplantation (SOT) and hematopoietic progenitor cell transplantation (HPCT).

Method: High-resolution HLA typing for HLA-A, B, C, DRB1, and DQB1 was conducted using a next generation sequencing (NGS) platform.

Results: The most frequent alleles observed among all HLAs were A*11:01:01 (0.1849), A*24:02:01 (0.1202) and A*01:01:01 (0.1143) in A locus, B*40:06:01 (0.1050), B*52:01:01 (0.0950) and B*51:01:01 (0.0723) in B locus, C*07:02:01 (0.1303), C*04:01:01 (0.1227) and C*15:02:01 (0.1185) in C locus, DRB1*07:01:01 (0.1286), DRB1*15:01:01 (0.1134) and DRB1*03:01:01 (0.0966) in DRB1 locus, and DQB1*06:01:01 (0.1849), DQB1*03:01:01 (0.1471) and DQB1*02:02:01 (0.0966) in DQB1 locus. The most frequent (>2 %) five-locus A ~ B ~ C ~ DRB1 ~ DQB1 haplotypes were A*33:03:01 ~ B*44:03:02 ~ C*07:06:01 ~ DQB1*02:02:01 ~ DRB1*07:01:01 (2.97 %), A*26:01:01 ~ B*08:01:01 ~ C*07:02:01 ~ DQB1*02:01:01 ~ DRB1*03:01:01 (2.23 %) and A*02:11:01 ~ B*40:06:01 ~ C*15:02:01 ~ DQB1*06:01:01 ~ DRB1*15:01:01(2.15 %). Among all tested loci, the HLA-B locus had the most polymorphism, whereas the HLA-DQB1 locus had the least polymorphism.

Conclusion: The data represent the distribution of HLA-A, B, C, DRB1, DQB1 alleles and their haplotype frequencies among the population in India.

Background: The cuproptosis is an intracellular copper (Cu) accumulation triggering the aggregation of mitochondrial lipoylated proteins and destabilization of iron‑sulfur (FeS) cluster proteins, leading to cell death. This copper-triggered modality of mitochondrial cell death has been associated with cuproptosis-related signature key genes (CRGs). Our study focused on the relationship between the cuproptosis CRGs and diabetic nephropathy (DN) to understand how such immune microenvironment may influence DN.

Methods: We downloaded and compared RNA sequencing data sets of DN glomerular tissue samples vs. normal renal tissue samples (GSE142025, GSE30528, and GSE96804) from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between DN and control samples were screened. Immune cell subtypes infiltration and immune score were figured out via different algorithms. Consensus clustering was performed by the Ward's method to determine different phenotypes of DN. CRG key genes between two phenotypes were identified via machine learning algorithm. Logistic regression analysis was applied to establish a nomogram for assessing the risk of DN.

Results: In DN samples, two genes NLRP3 and CDKN2A were positively correlated to the immune score. In contrast, six genes NFE2L2, LIAS, LIPT1, DLD, DBT and DLST were negatively correlated to the immune score. Via Consensus clustering based on cuproptosis CRG key genes, the DN samples were divided into cluster C1 and cluster C2. The cluster C1 was characterized by low cuproptosis CRG genes expression, high immune cell subtypes infiltration, and high enrichment of immune-related pathways. Cluster C2 was on the contrary, the Dicarbonyl/l-xylulose reductase (DCXR) and heat-responsive protein 12 (HRSP12) genes were related to clinical traits and the immune microenvironment, negatively correlated with most immune cell subtypes. The nomogram was constructed based on DCXR and HRSP12 showing good efficiency for the DN diagnosis.

Conclusion: We conclude that the immune microenvironment imbalance and metabolic disorders lead to the occurrence of DN. The signature cuproptosis genes, regulating the immune microenvironment and metabolism, represented the DN disease clustering to describe the heterogeneity and characterize immune microenvironment. Both HRSP12 and DCXR key genes are related to DN disease phenotypes and immune microenvironment characteristic and may help in DN diagnosis.

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare but severe complication following solid organ transplantation (SOT). Currently, treatment regimens still lack clear guidelines.

Methods: A kidney transplant recipient with PCNS-PTLD was reported in this case study, who treated with rituximab after transplant surgery. What's more, PubMed was used to find case series related to PCNS-PTLD.

Results: The patient of this case report experienced complete remission (CR) following resection and treatment with rituximab. A total of 130 cases were extracted from 20 articles and were combined with one case from our institution. Out of 131 patients with PCNS-PTLD, the median duration between SOT and PTLD was 48 months. The majority (83 %) of patients had received a kidney transplant, with 74.8 % showing monomorphic histology and 93 % having an EBV+ tumor. Most patients (95 %) had reduction in immunosuppression as part of their first-line treatment. Other initial treatments consisted of high-dose methotrexate (HD-MTX) (46 %), high-dose cytarabine (HDAC) (26 %), and/or rituximab (47 %). The Overall Response Rate (ORR) was 63 %, showing that HD-MTX and/or HDAC-based therapy had the highest rates of ORR and CR. Roughly half of the participants experienced prolonged survival. After 36 months of observation, the median progression free survival (PFS) was 10 months and the overall survival (OS) was 18 months.

Conclusion: The use of HD-MTX and HDAC showed promise in treating PCNS-PTLD, but rituximab may also a potential drug for the PCNS-PTLD. Research should continue to investigate the alternative treatments for this condition.

Background: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Studies have shown that mitochondrial damage is involved in the pathogenesis of AKI, and that inhibition of Hsp90 expression can improve IR-induced AKI. However, the mechanisms by which Hsp90 improves IR-induced AKI and whether it is involved in mitochondrial autophagy remain unclear.

Methods: An IR-induced AKI mouse model was established, and the degree of renal injury was analyzed using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The expression of Hsp90, HIF-1α, BNIP3, and mitochondrial autophagy proteins was detected by western blotting in vivo and in vitro. HK2 cell viability, apoptosis, mitochondrial autophagy, reactive oxygen species (ROS), and inflammatory cytokines levels were detected using Cell Counting Kit 8 (CCK8) assays, Terminal·deoxynucleotidyl transferase-mediated dUTP nick end·labeling (TUNEL) labeling, immunofluorescence, and enzyme-linked immunosorbent (ELISA).

Results: A murine IR-induced AKI model was successfully generated, and increased expression levels of Hsp90, HIF-1α, and inflammatory cytokines were observed, accompanied by a worsening of renal injury. After induction of IRI in HK2 cells, downregulation of Hsp90 or HIF-1α expression resulted in decreased downstream BNIP3 expression, an increase in HK2 cell viability, and a decrease in the level of mitochondrial autophagy.

Conclusion: Hsp90 upregulated the expression of HIF-1αand BNIP3, thereby enhancing mitochondrial autophagy in IR-induced AKI.

Ex-vivo depletion of donor CD45RA+ naïve T-cells can reduce graft-versus-host-disease (GVHD) in haploidentical hematopoietic stem cell transplantation (HSCT) while providing memory T-cells to reduce infections. CD62L is another marker of naïve T-cells. Depletion of CD62L+ cells may offer advantages of removing central memory T-cells which may also cause mild GVHD, and retain CD45RA+ effector memory T-cells (TEMRA). We aimed to evaluate the depletion efficiency, safety and immunoreconstitution after novel CD62L depleted donor lymphocyte infusion (DLI) with T-cell receptor (TCR)-αβ depleted haploidentical HSCT. Children with malignant or non-malignant diseases who underwent the first TCRαβ depleted haploidentical HSCT were recruited to receive CD62L depleted DLI on day 0 at a dose of 1 × 10⁶/kg or 5 × 10⁶/kg CD3 + CD62L- cells using the CliniMACS device. Six children aged 0.3-15 years received 4.6-10 × 10⁶/kg CD34+ cells. CD62L depletion resulted in undetectable CD3 + CD62L+ cells in 4 patients and 3.39-3.52 log reduction in 2 patients. Infusion was well-tolerated. All patients had neutrophil and platelet engrafted early (medians 10 and 9.5 days respectively) with 100 % donor chimerism. Only one patient had grade 1 acute GVHD. None had chronic GVHD. Post-transplant recovery of CD3+ cells reached a median of 117/uL at 1 month and as high as 352/uL at 3 months. TEMRA cells were present at 1 month (median 2 cells/uL) and increased 3 months post-transplant (median 21 cells/uL). In conclusion, CD62L depletion is highly efficient and appears safe and does not affect engraftment. It provides TEMRA and effector memory T-cells to protect the recipient against infections. Risk of GVHD is low.

Tacrolimus is a backbone for immunosuppression after allogeneic stem cell transplantation (AlloSCT). There is no sufficient kinetic data demonstrating the consistency of maintaining therapeutic levels. Herein, we measured the kinetic of therapeutic range (TTR) and its impact on outcomes of AlloSCT. Our local observational cohort included 186 adult AlloSCT performed at Hospital Austral between January 2012 and December 2019. An additional external cohort included 307 adult patients with AlloSCT from the University of Utah. We defined adequate TTR as >75 % of the measurements between 5.0 and 15.0 ng/mL during the first 30 days post-transplantation. In our local cohort, 55 % of patients had adequate TTR values. Primary graft failure was significantly lower in patients with adequate TTR (2 %, 95 % CI 0.5-7.7 % vs. 10 %, 95 % CI 5-18 %, p = 0.01). Non relapse mortality (NRM) was significantly lower with adequate TTR (17 %, 95 % CI 11-26 % vs. 33 %, 95 % CI 24-43 %; p < 0.01). Similarly, the external cohort had an NRM value significantly reduced in patients with adequate TTR values. In the pooled data analysis of local and external groups (n = 493), the TTR value below minimal range (≥25 % of measurements <5 ng/mL) was an independent risk factor for graft failure, as well as for NRM rate (44 %, 95 % CI 30-57 % vs. 18 %, 95 % CI 15-22 %) (p < 0.001) and lower OS at 3 years (47 %, 95 % CI 26-55 % vs. 56 %, 95 % CI 49-59 %, p < 0.001). These findings showed the importance of adequate TTRs during the first month after AlloSCTs. Sub-therapeutic TTR values were associated with worse survival outcomes.

Background: Autologous stem cell transplantation (ASCT) imposes significant immunogenic effects that may also underlie some of its anti-tumor effectiveness. Despite improvements in disease risk stratification and treatment approaches with high cure and response rate for newly diagnosed Hodgkin lymphoma (HL) with initial therapy in most patients, a significant proportion will be experiencing refractory or relapsed (R/R) following the initial front-line therapy. A high-dose chemotherapy followed by ASCT remains the standard treatment for relapsed Hodgkin disease in adult patients. The aim of our study was to identify the impact of ASCT on outcomes in R/R HL, considering various pre- and post-ASCT parameters as prognostic predictors, including disease status response, time of absolute neutrophils, and lymphocyte recovery counts post ASCT.

Methods: We retrospectively investigated data of 118 patients with R/RHL from January 2014 to December 2022, whose ages ranged from 7 to 58 years old. The recorded data included: the early response type and mortality rate, at day 100 post-ASCT, as well as the end of the study outcomes such as survival, relapse, and mortality status. Patients were grouped according to gender, disease status pre-ASCT, number of chemotherapy protocols that were given pre-ASCT, time of absolute neutrophils and lymphocyte recovery counts post-ASCT.

Results: The mean age of our included patients was 25.1 (7-58) years. The male to female ratio was1.2:1with a mean duration of disease follow-up was 74.2 months. The mean duration time of absolute neutrophil and lymphocyte recovery count post-ASCT day was 11 ± 2.9 and 13 ± 2.6 days respectively. The outcome at 100 days post-ASCT was: 89.8 % of the patients showed complete remission, 6.8 % showed no response, and 3.4 % deceased. The three-year overall survival (OS) rate was 88.5 %, while the event free survival (EFS) rate was 72 %. Regarding the three-year EFS rate for patient with complete remission was 91 %, for patients with uncertain complete response was 71 %, also 71 % for partial remission and 45 % for stable disease. The EFS rate in relation to the number of chemotherapy protocols at three-year follow up was 80 % and 66 % for patients with ≥2 chemotherapy lines(P = 0.03).

Conclusion: Autologous stem cell transplantation for R/R HL patients demonstrated a significant favorable outcome in terms of the overall survival rate and the progression-free disease, especially among those who exhibited earlier response to salvage chemotherapy at the pre-transplantation stage and unrelated to time of absolute neutrophil and lymphocyte recovery count.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder primarily distinguished by synovial inflammation, which, as the disease evolves, can lead to bone erosion and destruction. Consequently, the pivotal strategy in preventing joint damage and fostering functional recovery lies in the effective management of synovial inflammation. Disease-modifying antirheumatic drugs (DMARDs) and prednisone therapy remain the first-line treatments for RA. However, in instances of refractory RA, these medications may fall short in adequately controlling inflammation, and they are often accompanied by several adverse effects, including limited bioavailability, therapeutic resistance, and potentially toxic side effects. Given these challenges, the identification of targeted therapies to manage disease activity and diminish inflammation becomes imperative.Recently, biologic agents for the treatment of RA have garnered significant attention owing to their minimal side effect profile, reduced potential for drug dependence, and their precise therapeutic action directly on target cells. This review provides a comprehensive exploration of advancements in biologics that target and inhibit inflammatory cytokine receptors, specifically TNF-α, IL-6, and IL-1β, as well as B lymphocyte receptors, TLR4, nanodrugs, and Janus kinase (JAK) inhibitors in the context of RA. By providing innovative perspectives and strategies for the treatment of this condition, this review contributes to the ongoing efforts to refine and improve the therapeutic landscape for RA.