BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

OBJECTIVES: To investigate the characteristics of immune cell infiltration in tumor samples from Chinese patients with clear cell renal cell carcinoma (ccRCC) and the correlation of immune cell infiltration with tumor stage and response to immunotherapy. METHODS: Tumor samples and clinicopathological data were collected from 154 ccRCC patients treated in Nanfang Hospital, Southern Medical University from October, 2020 to October, 2023. The immune cell types infiltrating the tumor tissues were identified using immunohistochemistry and immunofluorescence staining, and their correlations with the patients' clinicopathological characteristics were analyzed. Patient-derived tumor tissue fragment models (PDTF) models, constructed using tumor tissues from 22 patients, were treated with PD-1 monoclonal antibody, and T cell activation was detected using flow cytometry to assess the patients' responses to immunotherapy. RESULTS: In Chinese ccRCC patients included in this study, CD8⁺ T cells, CD4⁺ T cells, and CD3⁺ T cells were the most abundant in the tumor tissues. Higher infiltration levels of CD3⁺ T cells (P=0.004), PD-1⁺ T cells (P=0.020), CD68⁺ T cells (P=0.049), CD79⁺ T cells (P=0.049), and Tryptase⁺ cells (P=0.049) were all positively correlated with a larger tumor size (≥5 cm). A higher infiltration level of CD4⁺ T cells was associated with a lower tumor stage. Patients with higher International Society of Urological Pathology (ISUP) grades had higher infiltration levels of CD3⁺ T cells (P=0.023), CD8⁺ T cells (P=0.045), PD-1⁺ T cells (P=0.014), CD20⁺ B cells (P=0.020) and CD79⁺ B cells (P=0.049), and lower levels of Tryptase⁺ cells (P=0.001). Patients with abundant infiltrating immune cells tended to have better responses to immunotherapy. CONCLUSIONS The infiltrating immune cells are heterogeneous in Chinese ccRCC patients, and immune cell infiltration characteristics are closely correlated with clinicopathological parameters of the patients.
Humans ; Carcinoma, Renal Cell/pathology* ; Kidney Neoplasms/pathology* ; Immunotherapy ; Male ; Lymphocytes, Tumor-Infiltrating/immunology* ; Female ; Middle Aged ; CD8-Positive T-Lymphocytes/immunology* ; Aged ; T-Lymphocytes/immunology* ; Programmed Cell Death 1 Receptor/immunology* ; Adult ; CD4-Positive T-Lymphocytes/immunology* ; Neoplasm Staging

Tripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.
A549 Cells ; Animals ; Apoptosis Regulatory Proteins/immunology* ; DEAD Box Protein 58/immunology* ; Dogs ; HEK293 Cells ; Humans ; Influenza A Virus, H1N1 Subtype/immunology* ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Knockout ; Orthomyxoviridae Infections/pathology* ; Proteolysis ; RAW 264.7 Cells ; Signal Transduction/immunology* ; THP-1 Cells ; TNF Receptor-Associated Factor 3/immunology* ; Ubiquitination/immunology* ; Viral Proteins/immunology*

OBJECTIVE: To investigate the antitumor activity of decoction and study its liver and kidney toxicity and its effect on the immune system in a tumor-bearing mouse model. METHODS: Hepatoma H22 tumor-bearing mouse models were randomized into model group, cyclophosphamide (CTX) group, and low-, moderate-, and high-dose decoction groups (JW-L, JW-M, and JW-H groups, respectively). The antitumor activity of decoction was assessed by calculating the tumor inhibition rate and pathological observation of the tumor tissues. Immunohistochemistry was used to detect the expressions of Bax, Bcl-2, Bax/Bcl-2 and caspase-3 in the tumors. The liver and kidney toxicity of decoction was analyzed by evaluating the biochemical indicators of liver and kidney functions. The immune function of the tumor-bearing mice were assessed by calculating the immune organ index, testing peripheral blood routines, and detection of serum IL-2 and TNF-α levels using enzyme-linked immunosorbent assay. RESULTS: Compared with that in the model group, the tumor mass in CTX, JW-M and JW-H groups were all significantly reduced ( < 0.05) with cell rupture and necrosis in the tumors. Immunohistochemistry revealed obviously up-regulated expressions of Bax and caspase-3 and down- regulated expression of Bcl-2 protein with an increased Bax/Bcl-2 ratio in CTX, JW-M and JW-H groups. Treatment with decoction significantly reduced Cr, BUN, AST and ALT levels, improved the immune organ index, increased peripheral blood leukocytes, erythrocytes and hemoglobin levels, and up-regulated the levels of TNF-α and IL-2 in the tumor-bearing mice. These changes were especially significant in JW-H group when compared with the parameters in the model group ( < 0.01). CONCLUSIONS decoction has a strong anti-tumor activity and can improve the liver and kidney functions of tumor-bearing mice. Its anti-tumor effect may be attributed to the up-regulation of Bax, caspase-3, TNF-α and IL-2 levels and the down-regulation of Bcl-2 expression as well as the enhancement of the non-specific immune function.
Animals ; Antineoplastic Agents, Phytogenic ; pharmacology ; Carcinoma, Hepatocellular ; drug therapy ; immunology ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Kidney ; drug effects ; Liver ; drug effects ; pathology ; Liver Neoplasms ; drug therapy ; immunology ; metabolism ; pathology ; Mice ; Necrosis ; Neoplasm Proteins ; metabolism ; Random Allocation ; Up-Regulation

Cytosolic retinoic acid-inducible gene I (RIG-I) is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β (IFN-β). Innate immune response to hepatitis B virus (HBV) plays a pivotal role in viral clearance and persistence. However, knowledge of the role that RIG-I plays in HBV infection is limited. The woodchuck is a valuable model for studying HBV infection. To characterize the molecular basis of woodchuck RIG-I (wRIG-I), we analyzed the complete coding sequences (CDSs) of wRIG-I, containing 2778 base pairs that encode 925 amino acids. The deduced wRIG-I protein was 106.847 kD with a theoretical isoelectric point (pI) of 6.07, and contained three important functional structures [caspase activation and recruitment domains (CARDs), DExD/H-box helicases, and a repressor domain (RD)]. In woodchuck fibroblastoma cell line (WH12/6), wRIG-I-targeted small interfering RNA (siRNA) down-regulated RIG-I and its downstrean effector-IFN-β transcripts under RIG-I' ligand, 5'-ppp double stranded RNA (dsRNA) stimulation. We also measured mRNA levels of wRIG-I in different tissues from healthy woodchucks and in the livers from woodchuck hepatitis virus (WHV)-infected woodchucks. The basal expression levels of wRIG-I were abundant in the kidney and liver. Importantly, wRIG-I was significantly up-regulated in acutely infected woodchuck livers, suggesting that RIG-I might be involved in WHV infection. These results may characterize RIG-I in the woodchuck model, providing a strong basis for further study on RIG-I-mediated innate immunity in HBV infection.
Animals ; Cell Line, Tumor ; Cloning, Molecular ; DEAD Box Protein 58 ; antagonists & inhibitors ; genetics ; immunology ; Fibroblasts ; immunology ; pathology ; Gene Expression ; Hepatitis B ; genetics ; immunology ; pathology ; veterinary ; Hepatitis B Virus, Woodchuck ; Immunity, Innate ; Interferon-beta ; genetics ; immunology ; Isoelectric Point ; Kidney ; immunology ; pathology ; virology ; Liver ; immunology ; pathology ; virology ; Marmota ; genetics ; immunology ; virology ; Open Reading Frames ; Protein Domains ; RNA, Double-Stranded ; RNA, Small Interfering ; genetics ; metabolism ; Rodent Diseases ; genetics ; immunology ; pathology ; virology

BACKGROUND: Angiotensin II type 1 receptor (AT1R) is responsible for cardiovascular effects mediated by angiotensin II. This study aimed to investigate the impact of antibodies directed against AT1R (anti-AT1R) in renal allograft rejection. METHODS: We evaluated 53 patients who had biopsy-proven rejection including antibody-mediated rejection (AMR) (N=22), T-cell-mediated rejection (TCMR) (N=29), and mixed AMR and TCMR (N=2). Donor specific HLA antibodies (DSA) and anti-AT1Rs were simultaneously determined. RESULTS: Anti-AT1Rs were detected in 9.4% (5/53) of rejection patients (one with acute AMR, two with chronic active AMR, one with acute TCMR, and one with mixed acute AMR & TCMR). HLA antibodies and DSA were detected in 75.5% (40/53) and 49.1% (26/53) of patients, respectively. There was no significant difference in transplant characteristics between anti-AT1R(+) and anti-AT1R(-) patients except for the association of HLA class-I DSA(+) and anti-AT1R(+). Four of five anti-AT1R(+) patients had DSA and were also found to have AMR. A single anti-AT1R(+)/DSA(-) patient developed acute TCMR. Detection rates of DSA, HLA antibodies, or anti-AT1R were not different between AMR and TCMR. However, DSA(+)/anti-AT1R(+) was more frequently found in AMR than in TCMR (P=0.036). Patients with anti-AT1R showed a greater tendency to develop high-grade rejection as Banff IIA/IIB or AMR. CONCLUSIONS: The presence of anti-AT1R was significantly associated with HLA class-I DSA in renal allograft rejection patients. Both anti-AT1R and DSA positivity was associated with AMR in patients with renal allograft rejection.
Adult ; Antibodies/blood ; Female ; Graft Rejection/*etiology ; HLA Antigens/immunology ; Humans ; Kidney/pathology ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Receptor, Angiotensin, Type 1/*immunology ; Tissue Donors ; Transplantation, Homologous

Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid.
Acute Disease ; Acute Kidney Injury/complications/*drug therapy/pathology ; Anti-Bacterial Agents/therapeutic use ; Azithromycin/therapeutic use ; Bacteremia/*drug therapy/microbiology/pathology ; Cefotaxime/therapeutic use ; Creatinine/blood ; Escherichia coli ; Escherichia coli Infections/*drug therapy/microbiology/pathology ; Female ; Humans ; Kidney/pathology ; Methylprednisolone/therapeutic use ; Middle Aged ; Nephritis, Interstitial/*drug therapy/immunology/pathology ; Pyelonephritis/complications/*drug therapy/pathology ; Renal Dialysis ; Shock, Septic/drug therapy/microbiology

PURPOSE: To evaluate tumor-specific immunity and define the mechanisms involved in the cryoimmunologic response, we compared the tumor control efficacy and immunologic responses of cryoablation with those of surgical excision in a tumor rechallenge model. MATERIALS AND METHODS: Sixty BALB/c mice with RENCA tumors that were generated in the left flank area underwent cryoablation or radical excision. The mice successfully treated were rechallenged with RENCA or an undifferentiated colon carcinoma cell line, CT26, in the contralateral right flank area. The recurrence rate after tumor rechallenge in each group was then observed. To assess the immunologic response of each treatment modality, fluorescent-activated cell sorting (FACS) analysis and a cytotoxicity assay using 51Cr release were performed. RESULTS: After reinoculation of the RENCA cells, the rate of tumor growth was significantly higher in the surgical excision group than in the cryoablation group (94.4% vs. 11.1%, p=0.001). In the cryoablation group, the tumor growth rate was significantly increased after rechallenge of CT26 cells compared with RENCA (94.1% vs. 11.1%, p=0.001). The cryoablation group showed an elevated CD3, CD4, CD8 T, and natural killer cell count in the FACS analysis and also showed significantly increased cytotoxicity in the 51Cr release assay compared with the excision group. CONCLUSIONS: These results showed that cryoablation, compared to surgical resection, was more effective in preventing tumor growth after rechallenge with RENCA cells and that this response was tumor-specific, because the CT26 cells did not have the same effect.
Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Renal Cell/*immunology/pathology/*surgery ; Cell Death ; Cryosurgery/*methods ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Kidney Neoplasms/*immunology/pathology/*surgery ; Lymphocyte Count ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice, Inbred BALB C ; Neoplasm Recurrence, Local/immunology ; Neoplasm Transplantation

OBJECTIVETo study the clinicopathologic characteristics of IgG4-related disease in the orbital and periorbital tissue.

METHODSThe clinical manifestations and pathologic features of 17 cases of IgG4-related disease affecting the orbital and periorbital tissue encountered during the period from 2012 to 2013 were studied.

RESULTSThere were 9 male patients and 8 female patients. The age of patients ranged from 11 to 71 years (mean = 48.5 years). The main clinical manifestation was swelling of the eyelids: bilateral in 11 patients and unilateral in 6 patients. The duration of disease ranged from 5 months to 7 years (more than 2 years in 13 cases). Six patients had history of allergic disorders. In addition to orbital/periorbital involvement, the disease also affected salivary gland, lymph node, lung and kidney. The disease relapsed in 9 patients. Amongst the 8 patients treated with steroids, 5 of them achieved complete remission and the remaining 3 patients had partial remission. The IgG4 level of the 17 cases ranged from 1.49 to 14.88 g/L. Histologic examination showed pseudolymphoma pattern in 8 cases, mixed pattern in 8 cases and sclerotic pattern in 1 case. There were various degrees of lymphoplasmacytic infiltrates (with lymphoid follicle formation) and stromal fibrosis. Classical obliterative phlebitis was absent. Tissue eosinophilia was demonstrated in the 17 cases studied. Immunohistochemical study showed the presence of more than 50 IgG4-positive plasma cells per high-power field, with IgG4/IgG plasma cells ratio more than 40%.

CONCLUSIONThere are characteristic clinical manifestations, pathologic features and laboratory findings in orbital and periorbital IgG4-related disease. Thorough understanding is important in arriving at a correct diagnosis.

Adult ; Aged ; Autoimmune Diseases ; immunology ; pathology ; Child ; Female ; Humans ; Immunoglobulin G ; Kidney Diseases ; immunology ; pathology ; Lung Diseases ; immunology ; pathology ; Lymphatic Diseases ; immunology ; pathology ; Male ; Middle Aged ; Orbital Diseases ; immunology ; pathology ; Plasma Cells ; immunology

OBJECTIVETo investigate the clinical characteristics, renal pathology, treatment and prognosis of children with atypical hemolytic uremic syndrome associated with H factor antibody.

METHODFour children less than 18 yr of age admitted from Nov. 2010 to May 2011 in Peking University First Hospital were included. They all met the criteria for atypical hemolytic uremic syndrome and with positive serum anti factor H antibody. They aged from 5 to 11 yr. Data on clinical manifestations, renal pathology, treatment and prognosis were analyzed.

RESULTAll of the 4 cases had gastrointestinal symptoms such as vomiting, abdominal pain, or abdominal distension. None of them had diarrhea. Two children had hypertension. One child had episodes of convulsion. One child had history of atypical hemolytic uremic syndrome. All of them had low serum complement C3. Three of them had low serum factor H (38.0, 88.4, 209.4 mg/L). All of them had serum antibody to factor H (1: 7 068, 1: 1 110, 1: 174, and 1: 869). Three of them received renal biopsy, all of them showed thrombotic microangiopathy. All of them were treated with steroid combined with mycophenolate mofetil. Two children received plasma exchange. They were followed up for 8 to 29 months. The renal function became normal and proteinuria relieved in all of them. The serum factor H concentration increased to 405.8, 155.8 and 438.4 mg/L, respectively. The titer of anti factor H antibody decreased to 1: 119, 1: 170, 1: 123, and 1: 674, respectively.

CONCLUSIONGastrointestinal symptom is common in children with atypical hemolytic uremic syndrome associated with H factor antibody. Hypocomplementemia was observed in all of them. Steroid combined with mycophenolate mofetil seemed to be effective for them. The monitoring of serum factor H and antibody to factor H may help diagnosis and treatment.

Atypical Hemolytic Uremic Syndrome ; Autoantibodies ; blood ; immunology ; Child ; Child, Preschool ; Complement Factor H ; immunology ; Creatinine ; blood ; Female ; Hemolytic-Uremic Syndrome ; drug therapy ; immunology ; pathology ; Humans ; Kidney ; pathology ; physiopathology ; Kidney Function Tests ; Male ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Plasma Exchange ; Prednisolone ; administration & dosage ; therapeutic use ; Prognosis ; Retrospective Studies