Transplant immunology最新文献

Takayasu arteritis (TA) is a large-vessel vasculitis that rarely presents in infancy. Casitas B-lineage lymphoma (CBL) syndrome is a rare genetic disorder due to heterozygous CBL gene germline pathogenic variants that is characterized by a predisposition to develop juvenile myelomonocytic leukemia (JMML). Vasculitis, including TA, has been reported in several patients. Herein, we describe a patient with CBL syndrome, JMML, and TA, developing long-term remission of this vasculitis after allogeneic hematopoietic stem cell transplant (HSCT), and perform a literature review of CBL syndrome with vasculitis or vasculopathy. We report a female patient with growth delay, developmental issues, and congenital heart disease who was admitted at 14 months of age with massive splenomegaly, lymphadenopathy, fever, and hypertension. Body imaging studies revealed arterial stenosis and wall inflammation of the aorta and multiple thoracic and abdominal branches. Whole exome sequencing revealed a pathogenic variant in CBL with loss of heterozygosity in blood cells, diagnosing CBL syndrome, complicated by JMML and TA. Allogeneic HSCT induced remission of JMML and TA, permitting discontinuation of immunosuppression after 12 months. Six years later, her TA is in complete remission off therapy. A literature review identified 18 additional cases of CBL syndrome with vasculitis or vasculopathy. The pathogenesis of vasculitis in CBL syndrome appears to involve dysregulated T cell function and possibly increased angiogenesis. This case advances the understanding of vascular involvement in CBL syndrome and of the genetic, immune, and vascular interplay in TA, offering insights for treating CBL syndrome and broader TA.

Background

After organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients.

Methods

We included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR).

Results

The median age at the time of conversion was 68.9 years (range: 26.1–83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3–31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5–4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5–3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%.

Conclusion

The results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Background

Ischemia/reperfusion injury (IRI) can lead to acute kidney injury and result in high disability and mortality rates. Cystathionine γ-lyase (CSE)-produced hydrogen sulfide (H₂S) has been confirmed to play a protective role in renal IRI. While autophagy is involved in renal IRI, its role in the regulation by endoplasmic reticulum stress (ERS) has not been considered. Our study explored the role of CSE/H₂S in protecting against renal IRI by regulating ERS-induced autophagy.

Methods

C57/BL6 mice were subjected to 30-min renal ischemia followed by .24-h reperfusion injury (IRI). The H₂S donor sodium hydrosulfide hydrate (NaHS) or the CSE inhibitor D,L-propargylglycine (PAG) was injected intraperitoneally (i.p) into the mice. Serum creatinine and urea nitrogen levels were analyzed to evaluate renal function. Renal tubule epithelial cell damage was measured by HE and PAS staining. ERS and microtubule-associated protein light chain 3 (LC3) autophagy (LC3-I to LC3-II conversion) were analyzed by using western blotting.

Results

In a C57/BL6 mouse model of acute renal IRI, the application of IRI impaired the renal function, which was accompanied by elevated serum creatinine (P < 0.001) and urea nitrogen levels (P < 0.001). While NaHS pretreatment dramatically attenuated renal IRI, PAG administration exacerbated renal IRI (P < 0.001). Furthermore, NaHS treatment inhibited the ERS-induced increased LC3II/I protein ratio (P < 0.001); increased Beclin-1 protein expression (P < 0.001); PAG pretreatment exacerbated the effects of ERS on both the LC3II/I ratio (P < 0.001) and the Beclin-1 protein expression (P < 0.001).

Conclusions

Our results suggest that the CSE/H₂S system is an important therapeutic target for protecting against renal IRI, and it may protect renal tubule epithelial cells from IRI by suppressing ERS-induced autophagy.

Background

Post-transplant diabetes mellitus (PTDM) is a common complication after transplantation. We aim to explore potential risk factors of PTDM and its association with outcomes after lung transplantation (LTx).

Methods

A retrospective study was conducted in 100 patients who underwent LTx at our institution from 2017 to 2021. Patients' information was collected, and genotyping for single nucleotide polymorphisms known to potentially increase the risk of Type 2 DM was performed. Univariate and multivariate analyses were conducted to identify risk factors for PTDM. The primary outcome was the incidence of PTDM. Secondary outcomes were associations between PTDM and clinical outcomes following LTx.

Results

Thirty-nine patients (39.0%) developed PTDM, while 10 patients (25.6%) recovered subsequently. The incidence of PTDM was associated with age > 45 (HR: 2.919, 95% CI [1.021–8.348]), pre-transplant HbA1c > 5.7% (HR: 2.344, 95% CI [1.201–4.573]), KCNJ11 rs5215 (HR: 2.090, 95% CI [1.050–4.162]) and tacrolimus concentration > 8 ng/mL in the first month (HR: 2.090, 95% CI [1.050–4.162]). Patients with PTDM experienced elevated fasting blood glucose levels (FBG) during the first month post-transplantation (p < 0.001), and required a longer duration for FBG to return to normal levels (p < 0.001). However, the presence of PTDM did not significantly impact renal function, incidence of infection episodes, chronic lung allograft dysfunction or mortality following LTx.

Conclusion

Advanced age, elevated HbA1c levels, KCNJ11 gene polymorphism, and early exposure to tacrolimus are all significant risk factors for PTDM following LTx. The clinical implications of these factors warrant attention.

Background

Extended-release tacrolimus for prophylaxis of allograft rejection in heart transplant (HT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release (IR-) tacrolimus. We compared long-term efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients.

Methods

25 prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 3 years following transplant was compared between groups using non-inferiority analysis.

Results

LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 16% (90%CI, −37%, −1%, non-inferiority p = 0.002) up to 3 years following heart transplant. Up to 3-years post-transplant, 14 patients remained on once-daily LCPT and 10 patients were switched to IR-tacrolimus due to lack of insurance coverage. There were no significant differences in the rate of chronic kidney disease requiring dialysis, cytomegalovirus requiring treatment, cardiac allograft vasculopathy, and malignancy within 3 years following transplant.

Conclusion

LCPT is non-inferior in efficacy to IR-tacrolimus in heart transplantation with a similar safety profile. Narrowly-constrained FDA labels specific to kidney transplant remain a barrier to consistent access to many immunosuppressant medications for recipients of non-kidney solid organs. We recommend the FDA consider developing facile pathways for expanding the approved label of extended-release tacrolimus formulations to heart transplant recipients.

Background

Renal diseases have a significant negative impact on human health and the quality of life. Renal ischemia/reperfusion (I/R) injury is considered as one of the leading causes of renal dysfunction and tissue damage. Oxidative stress and inflammation are responsible for cellular apoptosis playing critical roles in renal I/R injury. Recent studies suggested that dapagliflozin—a medication used to treat Type 2 Diabetes—may exert protective effects on I/R injury in kidneys by alleviating oxidative stress and inflammation. Our study evaluated the protective effects of dapagliflozinon in renal I/R injury.

Methods

A group of 32 male Sprague-Dawley rats were divided into four groups: 1) control group without any manipulation; 2) sham-operated control group with surgery but without I/R injury; 3) experimental group with 30-min I/R injury; and 4) therapeutic group with 30-min IR injury and dapagliflozin therapy. The fourth therapeutic group received 1 mg/kg dapagliflozin delivered once daily by oral gavage. All rats were evaluated by measurements of neutrophil gelatinase-associated lipocalin (NGAL), creatinine kinase (CR), blood urea nitrogen (BUN), kidney injury molecule-1 (KIM-1), myoglobin (MYO), creatinine kinase (CK), lactate dehydrogenase (LDH) LD, GSH, superoxide dismutase (SOD), MDA, interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a and glutathione peroxidase (GSH-Px) levels. TUNEL and flow cytometry assays evaluated apoptosis.

Results

Overall, the 30-min exposure to I/R injury significantly elevated levels of NGAL, CR, BUN, CK, LDH, KIM-1, and MYO (all p < 0.05). Inflammatory cytokine levels (IL-6 and TNF-a) were also increased after I/R injury (p > 0.05). At the same time, I/R injury decreased levels of SOD and GSH-Px (p > 0.05). In contrast, administration of dapagliflozin following I/R injury reduced renal damage, enhanced antioxidant capacity, and suppressed inflammatory responses (all p > 0.05), thus improving renal function, while reducing oxidative stress status and inflammatory responses. Further investigations revealed that dapagliflozin exerted its protective effects on renal tissues by activating the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, inhibiting cellular apoptosis, and promoting proliferation and autophagy through bone morphogenetic protein 4 (BMP4).

Conclusion

These findings documented that dapagliflozin protected kidneys from I/R injury suggesting its therapeutic potential.

Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a high mortality rate and a wide range of symptoms. Solid organ transplantation, which provides patients with a unique immunosuppressive state, is a less common predisposing factor for HLH. HLH after solid organ transplantation (HLH-SOT) is very rare and fatal. It is hard to diagnose and treat and extremely understudied. The use of immunosuppressants makes the situation of HLH-SOT more complex. This review summarizes the existing literature on HLH after solid organ transplantation and describes its triggers and symptoms, focusing on its diagnosis and treatment. We performed a literature search of case reports, case series, letters to the editor, and clinical quizzes describing patients with HLH after solid organ transplantation (HLH-SOT). We provide recommendations on the diagnosis protocol and treatment strategy based on the existing evidence.

Background

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been identified as the potentially curative treatment for high-risk acute lymphoblastic leukemia (ALL) in adult patients. However, relapse of the disease and/or development of graft-versus-host disease (GVHD) remain to be the most common barriers for successful allo-HSCT. Preclinical studies showed that ruxolitinib, a Janus tyrosine kinase (Jak)1 and Jak2 inhibitor, has a selective anti-GVHD effects while preserving a potent graft-versus-leukemia (GVL) effect. Our study aimed to investigate the efficacy and safety in early application of ruxolitinib for the high-risk ALL patients to prevent GVHD.

Methods

There were eight patients undergoing allo-HSCT at the Bone Marrow Transplantation Center of the Third Xiangya Hospital of Central South University between April 2020 and April 2021. Ruxolitinib (5–10 mg twice daily) was administered early (median time: 45 days) after stem cell infusion.

Results

After a median follow-up of 14 months (range from 8 to 18 months), the ALL disease relapse occurred in two cases. Among all eight patients, two of them developed grade I/II acute (a) GVHD, while no patient developed grade III/IV aGVHD, and one patient developed chronic (c) GVHD. As for the virus activation, no patient developed EBV activation or EBV related lymphoproliferative disease, and three patients developed CMV activation. Our results suggest that the early application of ruxolitinib could safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, it may have a limited effect on preventing the recurrence of high-risk ALL and thus may require additional therapy with other anti-relapse drugs.

Conclusions

Our preliminary observations suggest that an early application of ruxolitinib can safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, ruxolitinib may have a limited effect on preventing the ALL recurrence of high-risk patients.

Introduction

Hematopoietic Stem Cell Transplant (HSCT) is currently an important curative treatment for many patients with malignant and non-malignant diseases. Graft versus host disease (GVHD) represents a major complication in allogeneic HSCT recipients. Several polymorphisms in cytokine genes have recently been investigated as candidates for risk factors for acute-GVHD (aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Objective

In this study, we analyzed specific interleukin (IL)-10 haplotypes polymorphisms, in a cohort of 99 patients and their respective allo-HSCT donors for aGVHD and risk.

Results

An association was found between IL-10 promoter haplotype polymorphisms at positions −1082, −819 and − 592 with the occurrence of aGVHD. Patients who have the GCC/GCC haplotype are at increased risk of aGVHD (P = 0.017, HR: 5.42 (95% CI: 1.34–21.84). In the donors group and severity of aGVHD as not found statistical significancy.

Conclusion

The results obtained show the IL-10 GCC/GCC haplotype can be an important biomarker to identify the greatest risk of aGVHD in the patient undergoing HSCT.

Background

IgA nephropathy is a renal lesion in patients with end-stage liver disease, called hepatic IgA nephropathy. The common manifestation of hepatic IgA nephropathy is microscopic hematuria. Sirolimus, often used to prevent organ rejection, has been reported to induce proteinuria after organ transplantation. But few cases of nephrotic proteinuria and hematuria are reported.

Case presentation

In this case, a 45-year-old male with a long history of hepatic B virus infection and liver cirrhosis, received liver transplant and was taking sirolimus as one of his immunosuppression drugs. Overt proteinuria and hematuria occurred. With no proteinuria history before, renal biopsy was performed, which indicated IgA nephropathy.

Conclusion

We reported a liver recipient, who was taking sirolimus, developing nephrotic proteinuria and hematuria with IgA nephropathy. Further studies need to be carried out to disclose mechanism behind this phenomenon.