Organ transplantation is an effective alternative treatment for patients with end-stage organ failure. However, the shortage of donor organs has limited the widespread application of clinical transplantation. In recent years, breakthroughs in CRISPR-Cas9 gene editing technology have overcome the barrier of hyperacute rejection in xenotransplantation, offering a potential solution to the organ shortage crisis. Rejection remains a critical factor affecting graft survival. Antigen-presenting cells play a vital role in the initiation and progression of rejection and immune regulation in xenotransplantation. Therefore, in-depth investigation into the role of antigen-presenting cells in xenotransplantation is of great significance. This article summarizes the roles and therapeutic strategies of professional antigen-presenting cells, including macrophages, dendritic cells and B cells in xenotransplantation, aiming to provide insights for future research on immune regulation mechanisms in this field.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Objective:To summarize the diagnosis and treatment experience of kidney graft’s ureteral obstruction secondary to ureteral inguinal hernia.Methods:Clinical data of a patient with kidney graft’s ureteral obstruction secondary to ureteral inguinal hernia in the Second Xiangya Hospital of Central South University in December 2023 was retrospectively analyzed.This was a male patient with 44 years old. Eleven years after kidney transplantation, he was admitted to the hospital because his serum creatinine increased for one day, accompanied by oliguria and edema of both lower limbs. His previous basal creatinine was maintained in the range of 60-70 μmol/L. Physical examination showed a mass of about 4 cm×3 cm in the right groin. The patient complained of anuria lasting for 7 hours on the second day after admission, and the serum creatinine increased to 406 μmol/L. B-ultrasound showed obstruction of the transplanted kidney and ureteral hydrops. Abdominal CT scan suggested that the right inguinal hernia (transplanted kidney ureteral hernia) was suspected.Preoperative diagnosis of ureteral obstruction secondary to inguinal hernia of the transplanted kidney was made. Percutaneous nephrostomy was performed under local anesthesia, and postoperative anti-infection and indwelling catheter treatments were given. The serum creatinine dropped significantly and the inguinal mass disappeared. A follow-up color ultrasound showed that the transplanted kidney ureteral obstruction and hydrops were alleviated than before. The patient was discharged 2 days after the nephrostomy operation. He was recommended to visit the general surgeon for hernia repairment in a timely manner after a stable renal function was achieved. The patient's renal function basically returned to normal during the following 3 weeks after discharge, and no hernia repair was performed. He was then readmitted to the hospital in order to remove the nephrostomy tube. The patient's nephrostomy tube and urinary catheter both drained almost 1000ml every day. After being informed of the risk of recurrence of obstruction among others, the nephrostomy was removed. Oliguria occurred on the day of nephrostomy tube removal, slight swelling and pain in the transplanted kidney area, and recurrence mass in the groin was seen. The color ultrasound showed recurrence of hydroureteral obstruction and hydrops in the transplanted kidney, and a transplanted nephrostomy was performed again along the original stoma. The postoperative recovery was smooth. One week later, a MDT by general surgeons and the urologists were conducted for choices of surgery. Traditional inguinal hernia repair (Bassini method) and double J-tube insertion under flexible ureteroscope were performed. Results After the operation, anti-infection with cefuroxime, immunosuppression, wound dressing change were given among other treatments. The nephrostomy tube and urinary catheter were removed before discharge. The double J-tube was removed 2 months after discharge. The outpatient follow-up was carried out until 9 months after the initial nephrostomy. The follow-up serum creatinine was at 62 umol/L. The color Doppler ultrasound showed only localized fluid accumulation and no recurrence of ureteroinguinal hernia.Conclusions:Ureteral inguinal hernia of the transplanted kidney is rare and can lead to hydroureteral obstruction and renal insufficiency in the transplanted kidney. Abdominal CT examination is the first choice, combined with abdominal physical examination for diagnosis. Nephrostomy is an effective measure to relieve obstruction and promote recovery of renal function. Hernia repair surgery is an effective measure to prevent the recurrence of kidney graft’s ureteral inguinal hernia, and Bassini method hernia repair is a feasible treatment measure.

Objective:To summarize the diagnosis and treatment experience of kidney graft’s ureteral obstruction secondary to ureteral inguinal hernia.Methods:Clinical data of a patient with kidney graft’s ureteral obstruction secondary to ureteral inguinal hernia in the Second Xiangya Hospital of Central South University in December 2023 was retrospectively analyzed.This was a male patient with 44 years old. Eleven years after kidney transplantation, he was admitted to the hospital because his serum creatinine increased for one day, accompanied by oliguria and edema of both lower limbs. His previous basal creatinine was maintained in the range of 60-70 μmol/L. Physical examination showed a mass of about 4 cm×3 cm in the right groin. The patient complained of anuria lasting for 7 hours on the second day after admission, and the serum creatinine increased to 406 μmol/L. B-ultrasound showed obstruction of the transplanted kidney and ureteral hydrops. Abdominal CT scan suggested that the right inguinal hernia (transplanted kidney ureteral hernia) was suspected.Preoperative diagnosis of ureteral obstruction secondary to inguinal hernia of the transplanted kidney was made. Percutaneous nephrostomy was performed under local anesthesia, and postoperative anti-infection and indwelling catheter treatments were given. The serum creatinine dropped significantly and the inguinal mass disappeared. A follow-up color ultrasound showed that the transplanted kidney ureteral obstruction and hydrops were alleviated than before. The patient was discharged 2 days after the nephrostomy operation. He was recommended to visit the general surgeon for hernia repairment in a timely manner after a stable renal function was achieved. The patient's renal function basically returned to normal during the following 3 weeks after discharge, and no hernia repair was performed. He was then readmitted to the hospital in order to remove the nephrostomy tube. The patient's nephrostomy tube and urinary catheter both drained almost 1000ml every day. After being informed of the risk of recurrence of obstruction among others, the nephrostomy was removed. Oliguria occurred on the day of nephrostomy tube removal, slight swelling and pain in the transplanted kidney area, and recurrence mass in the groin was seen. The color ultrasound showed recurrence of hydroureteral obstruction and hydrops in the transplanted kidney, and a transplanted nephrostomy was performed again along the original stoma. The postoperative recovery was smooth. One week later, a MDT by general surgeons and the urologists were conducted for choices of surgery. Traditional inguinal hernia repair (Bassini method) and double J-tube insertion under flexible ureteroscope were performed. Results After the operation, anti-infection with cefuroxime, immunosuppression, wound dressing change were given among other treatments. The nephrostomy tube and urinary catheter were removed before discharge. The double J-tube was removed 2 months after discharge. The outpatient follow-up was carried out until 9 months after the initial nephrostomy. The follow-up serum creatinine was at 62 umol/L. The color Doppler ultrasound showed only localized fluid accumulation and no recurrence of ureteroinguinal hernia.Conclusions:Ureteral inguinal hernia of the transplanted kidney is rare and can lead to hydroureteral obstruction and renal insufficiency in the transplanted kidney. Abdominal CT examination is the first choice, combined with abdominal physical examination for diagnosis. Nephrostomy is an effective measure to relieve obstruction and promote recovery of renal function. Hernia repair surgery is an effective measure to prevent the recurrence of kidney graft’s ureteral inguinal hernia, and Bassini method hernia repair is a feasible treatment measure.

Objective To investigate the antigen presentation characteristics of dendritic cells(DC)and B cells in cardiac grafts.Methods The heart of BALB/c mice was transplanted into the abdominal cavity of C57BL/6J mice.CD45+cells in the heart graft were extracted and sorted by flow cytometry at postoperative 5 d,and single cell RNA sequencing was performed.Taking DC and B cell subsets in cardiac grafts as the main study cells,the changing trend,antigen presenting ability and intercellular communication with T cells after heart transplantation were analyzed by bioinformatics analysis and flow cytometry.Gene ontology(GO)function enrichment difference analysis was adopted to prove the specific function and the reliability annotation of cell subsets.Results Germinal center-like B cell(GC-L B)was the B cell subset with the largest increase in quantity during the acute rejection phase,accounting for 87％.Classical DC(cDC)2 was the only DC subset with a significant increase in quantity during acute rejection of heart transplantation,accounting for 44％of DC subset,and it occupied the highest communication intensity with T cells after heart transplantation.Mononucleated DC(moDC)and memory B cell(MBC)were the main transmitters of T cell input signals in non-transplanted hearts,whereas transformed into cDC2 and GC-L B during the acute rejection phase.Among them,MBC and GC-L B were the main sources of T cell input signals in non-transplanted hearts and heart grafts.Conclusions Compared with DC,B cells occupy a higher number and weight in the intercellular communication with T cells in non-transplanted hearts and heart grafts,prompting that the antigen presenting activity of B cells is more active and stronger than DC in the early stage of acute rejection of heart transplantation.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

Objective To investigate the effects of a 45％high-fat diet(HFD)with isocaloric intake on energy metabolism and endurance exercise capacity in SD rats.Methods Twenty-four male SD rats were randomly divided into normal chow diet group(CON),HFD group,normal chow diet+exercise training group(CONT),and HFD+exercise training group(HFDT).The CON and CONT groups received normal chow diet,while the HFD and HFDT groups received a 45％high-fat diet with isocaloric intake.The HFDT and CONT groups underwent an endurance training of moderate-intensity running for 6 weeks.Body weight,fat mass,and lean mass were measured weekly.Energy expenditure and basal metabolic rate during rest and exercise states were measured using Pheno Master/Calo Treadmill system.Blood glucose,lipids,and creatine kinase levels were detected after the exhaustion test.Results In 6 weeks after intervention,the endurance exercise capacity was significantly enhanced in the HFDT group than the CONT group(P＜0.05).There were no obvious differences in body weight and body composition among the groups under isoenergetic feeding conditions.At rest,no statistical differences were observed in total energy expenditure and basal metabolic rate among the groups.However,prior to the 4th week,the CON group primarily metabolized carbohydrates while the HFD group primarily metabolized fats.But the carbohydrate metabolism was decreased and then increased,and the substrate metabolism rates eventually reached similar levels between the 2 groups on the 5th to 6th week.The HFDT group primarily metabolized fats while the CONT group primarily metabolized carbohydrates,with significant differences persisting after 6 weeks of training(P＜0.05).HFD led to elevated levels of serum cholesterol,triglycerides(TG),and high-density lipoprotein cholesterol(HDL-C),but,endurance training resulted in decreased lipid levels in the HFDT group,accompanied by an increase inβ-hydroxybutyrate(βHB)level(P＜0.05).Isoenergetic diets had no significant differences in their effects on liver and kidney function or muscle damage indicators.Conclusion An isoenergetic HFD can improve fat utilization ability and extend endurance exercise time in rats without altering body composition or affecting liver and kidney function.

Objective To develop a nutritional formula on enhancing the endurance of heavy load exercise,and evaluate its efficacy comprehensively.Methods Sixty C57BL/6J male mice were randomly divided into control group(CON group)and low-,medium-and high-dose nutritional formula groups(LDF,MDF and HDF groups),with 15 mice in each group.Each group received intervention with nutritional formula at corresponding dose for 2 weeks,and underwent adaptive training and heavy load exercise in the 1 st and 2nd weeks,respectively.Exhaustion exercise time,skeletal muscle antioxidant indicators(SOD,MDA,PC and GSH),fatigue related indicators(serum URA,LDH and LA),muscle glycogen,and serum exercise injury related indicators(ALT,AST,CK and CK-MB)were measured and detected in the mice,and comprehensive evaluation was conducted according to relevant evaluation standards.Results The LDF group,MDF group and HDF group had significantly prolonged running exhaustion time than the CON group(P＜0.05),with the HDF group showing the greatest improvement(P＜0.05).Compared with the CON group,the activities of SOD and GSH in the skeletal muscles were significantly increased(P＜0.05),while the levels of MDA and PC in skeletal muscles were obviously decreased in the 3 doses of nutritional formula groups(P＜0.05).PAS staining of the skeletal muscles displayed that the glycogen content was significantly increased in the MDF group and the HDF group than the CON group(P＜0.05),and the highest increase was observed in the HDF group(P＜0.05).Biochemical test revealed that the levels of LDH,LA,ALT,AST,CK,and CK-MB were remarkably lower in the 3 doses of nutritional formula groups than the CON group(P＜0.05).Conclusion The nutritional formula can significantly improve the endurance and skeletal muscle antioxidant capacity in mice under heavy load exercise,and has anti-fatigue and-injury protection effects.This nutritional formula can be used to support physical fitness during heavy load endurance exercise.

Objective:The mouse kidney transplantation model presents challenges in terms of surgical difficulty and low success rate,making it difficult to master.This study aims to provide a crucial model for transplantation immunology research by modifying and developing novel techniques for mouse kidney transplantation. Methods:A total of 57 pairs of mice were used to establish and compare the modified and innovative surgical techniques for mouse kidney transplantation.Three different surgical models were established,including the abdominal suture technique for orthotopic kidney transplantation,the abdominal cuff technique for orthotopic kidney transplantation,and the cervical cuff technique for ectopic kidney transplantation.BALB/c or C57BL/6 male mice,aged 8 to 12 weeks and weighed 20 to 25 g with specified pathogen free-grade were served as the donor mice or the recipient mice.The surgical technique characteristics,key surgical times,complications,and pathological examination in the early postoperative period were summarized and compared. Results:Three different surgical models of mouse kidney transplantation were successfully established.The comparison of warm ischemic time for the 3 groups of mice showed no statistical significance(P=0.510 4).The abdominal suture group had the shortest total operation time of the donor compared with the abdominal cuff group and the cervical cuff group[(18.3±3.6)min vs(26.2±4.7)min and(22.8±2.5)min;both P<0.000 1].There was a significant difference in cold ischemia time among the 3 groups(all P<0.000 1),with(60.8±4.1)min in the cervical cuff group,(43.3±5.0)min in the abdominal suture group,and(88.8±6.7)min in the abdominal cuff group.Due to different anastomosis methods,the cervical cuff group had the shortest time[(17.6±2.7)min],whereas the abdominal cuff group had the longest time[(38.8±5.4)min].The total operation time for the recipients showed significant differences(P<0.000 1),with the abdominal suture group having the shortest time[(44.0±6.9)min],followed by the cervical cuff group[(64.1±5.2)min],and the abdominal cuff group[(80.0±6.0)min]being the longest.In the 32 mice of the abdominal suture group,there were 6 with intraoperative bleeding,including 1 arterial intimal injury bleeding and 5 with bleeding after vessel opening.Six mice had ureteral complications,including ureteral bladder anastomotic stenosis,necrosis,and renal pelvis dilation.Two mice had postoperative abdominal infections.In the abdominal cuff group,there was no intraoperative bleeding,but 6 mice showed mild arterial stenosis and 5 showed venous stenosis,4 arterial injury,4 arterial thrombosis,and 2 ureteral complications.No postoperative infections occurred in the mice.In the cervical cuff group,no intraoperative bleeding,arterial intimal injury,arterial/venous stenosis,or thrombosis were found in 13 mice.Five mice had ureteral complications,including ureteral necrosis and infection,which were the main complications in the cervical cuff group.The renal function in mice of the 3 groups remained stable 7 days after surgery.Hematoxylin and eosin staining and periodic acid-Schiff staining showed no significant differences in terms of acute rejection among the 3 surgical methods(all P>0.05). Conclusion:All 3 surgical methods are able to successfully establish mouse kidney transplantation models,with no significant differences observed in the short-term graft survival and acute rejection.The modified abdominal suture technique and abdominal cuff technique have their respective advantages in research applications.The novel cervical cuff technique for ectopic kidney transplantation model is relatively simple to be prepared and causes less trauma to the mice,providing more options for studies involving xenotransplantation,secondary transplantation,and local lymphatic drainage.However,the difficulty in harvesting the donor kidney and the high incidence of ureteral infections need further validation in long-term survival.This study holds important reference value for choosing the type of mouse kidney transplantation model for different research needs.