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

Epilepsy affects over 50 million people worldwide. Drug-resistant epilepsy (DRE) accounts for up to a third of these cases, and neuro-inflammation is thought to play a role in such cases. Despite being a long-debated issue in the field of DRE, the mechanisms underlying neuroinflammation have yet to be fully elucidated. The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics. Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes, such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis. The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems. We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application. We hope to provide an insightful overview to advance the quest for better DRE treatments.
Humans ; Drug Resistant Epilepsy/metabolism* ; Neuroinflammatory Diseases/immunology* ; Animals ; Brain/pathology* ; Nerve Net/pathology*

Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). This study investigates the role of high mobility group box 1 (HMGB1) in oligodendrocyte precursor cells (OPCs) in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier (BBB) by using OPC-specific HMGB1 knockout (KO) mice. We found that HMGB1 released from OPCs promotes BBB disruption, subsequently allowing increased immune cell infiltration. The migration of CD4+ T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes (OLs). OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS, leading to less damage to the myelin sheath and mitigated EAE progression. CD4+ T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs. Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; HMGB1 Protein/deficiency* ; Mice, Knockout ; Oligodendrocyte Precursor Cells/immunology* ; Mice, Inbred C57BL ; CD4-Positive T-Lymphocytes/immunology* ; Cell Movement ; Blood-Brain Barrier/immunology* ; Mice ; Myelin Sheath/pathology* ; Disease Models, Animal ; Coculture Techniques ; Oligodendroglia/metabolism* ; Female ; Cells, Cultured

Brain metastasis was a common metastasis site and leading cause of death in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors had improved survival of NSCLC patients with positive drive gene. It also brings good news to NSCLC patients with positive drive gene and brain metastases. However, there is still no effective treatment for NSCLC patients with drive gene-negative and brain metastases. In recent years, immunotherapy has made breakthrough progress and become important first and second line treatment options of NSCLC especially in patients with drive gene-negative. The role of immunotherapy in specific populations of NSCLC-brain metastasis patients, especially drive gene-negative patients has become the focus of attention. In this report, we review the research progress of immunotherapy in NSCLC with brain metastases, especially in driver-negative patients, analyze the limitations of existing research and future challenge.
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Brain Neoplasms ; immunology ; secondary ; therapy ; Carcinoma, Non-Small-Cell Lung ; genetics ; pathology ; Humans ; Immunotherapy ; methods ; Lung Neoplasms ; genetics ; pathology ; Patient Selection

In the present study, the use of dogs with experimental autoimmune encephalomyelitis (EAE) as a disease model for necrotizing encephalitis (NE) was assessed. Twelve healthy dogs were included in this study. Canine forebrain tissues (8 g), including white and grey matter, were homogenized with 4 mL of phosphate-buffered saline for 5 min in an ice bath. The suspension was emulsified with the same volume of Freund's complete adjuvant containing 1 mg/mL of killed Mycobacterium tuberculosis H37Ra. Under sedation, each dog was injected subcutaneously with canine brain homogenate at four sites: two in the inguinal and two in the axillary regions. A second injection (booster) was administered to all the dogs using the same procedure 7 days after the first injection. Clinical assessment, magnetic resonance imaging, cerebrospinal fluid analyses, necropsies, and histopathological and immunohistochemical examinations were performed for the dogs with EAE. Out of the 12 animals, seven (58%) developed clinically manifest EAE at various times after immunization. Characteristics of canine EAE models were very similar to canine NE, suggesting that canine EAE can be a disease model for NE in dogs.
Animals ; Brain/*pathology ; Disease Models, Animal ; Dog Diseases/*immunology ; Dogs ; Encephalitis/immunology/*veterinary ; Encephalomyelitis, Autoimmune, Experimental/immunology/*veterinary ; Female ; Fluorescent Antibody Technique/veterinary ; Immunization/veterinary ; Immunohistochemistry/veterinary ; Magnetic Resonance Imaging/veterinary ; Male ; Necrosis/immunology/*veterinary

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection.
Animals ; Brain/*pathology ; Disease Models, Animal ; Female ; Gene Expression Profiling ; Histocytochemistry ; *Immunocompromised Host ; Immunohistochemistry ; Interleukin-5/genetics ; Male ; Mice ; Parasite Load ; Toxocara canis/*immunology ; Toxocariasis/*immunology/*pathology

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection.
Animals ; Brain/*pathology ; Disease Models, Animal ; Female ; Gene Expression Profiling ; Histocytochemistry ; *Immunocompromised Host ; Immunohistochemistry ; Interleukin-5/genetics ; Male ; Mice ; Parasite Load ; Toxocara canis/*immunology ; Toxocariasis/*immunology/*pathology

Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid beta (Abeta) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Abeta production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.
Alzheimer Disease/immunology/pathology/*therapy ; Amyloid beta-Peptides/antagonists & inhibitors/immunology/metabolism ; Antibodies, Monoclonal/therapeutic use ; Brain/metabolism/pathology ; Humans ; Immunotherapy ; N-Methylaspartate/therapeutic use ; tau Proteins/antagonists & inhibitors/metabolism

Gliomas are extremely aggressive brain tumors with a very poor prognosis. One of the more promising strategies for the treatment of human gliomas is targeted immunotherapy where antigens that are unique to the tumors are exploited to generate vaccines. The approach, however, is complicated by the fact that human gliomas escape immune surveillance by creating an immune suppressed microenvironment. In order to oppose the glioma imposed immune suppression, molecules and pathways involved in immune cell maturation, expansion, and migration are under intensive clinical investigation as adjuvant therapy. Toll-like receptors (TLRs) mediate many of these functions in immune cell types, and TLR agonists, thus, are currently primary candidate molecules to be used as important adjuvants in a variety of cancers. In animal models for glioma, TLR agonists have exhibited antitumor properties by facilitating antigen presentation and stimulating innate and adaptive immunity. In clinical trials, several TLR agonists have achieved survival benefit, and many more trials are recruiting or ongoing. However, a second complicating factor is that TLRs are also expressed on cancer cells where they can participate instead in a variety of tumor promoting activities including cell growth, proliferation, invasion, migration, and even stem cell maintenance. TLR agonists can, therefore, possibly play dual roles in tumor biology. Here, how TLRs and TLR agonists function in glioma biology and in anti-glioma therapies is summarized in an effort to provide a current picture of the sophisticated relationship of glioma with the immune system and the implications for immunotherapy.
Animals ; Antigens, Neoplasm ; chemistry ; immunology ; Antineoplastic Agents ; chemistry ; immunology ; therapeutic use ; Brain Neoplasms ; genetics ; immunology ; pathology ; therapy ; Chemotherapy, Adjuvant ; Clinical Trials as Topic ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; drug effects ; immunology ; Glioma ; genetics ; immunology ; pathology ; therapy ; Humans ; Immunotherapy ; methods ; Signal Transduction ; Toll-Like Receptors ; agonists ; genetics ; immunology

To determine alteration of immune responses during visceral larva migrans (VLM) caused by Toxascaris leonina at several time points, we experimentally infected mice with embryonated eggs of T. leonina and measured T-helper (Th) cell-related serial cytokine production after infection. At day 5 post infection (PI), most larvae were detected from the lungs, spleen, intestine, and muscle. Expression of thymic stromal lymphopoietin (TSLP) and CCL11 (eotaxin) showed a significant increase in most infected organs, except the intestine. However, expression of the CXCL1 (Gro-alpha) gene was most highly enhanced in the intestine at day 14 PI. Th1-related cytokine secretion of splenocytes showed increases at day 28 PI, and the level showed a decrease at day 42 PI. Th2-related cytokine secretion of splenocytes also showed an increase after infection; in particular, IL-5 level showed a significant increase at day 14 PI, and the level showed a decrease at day 28 PI. However, levels of Th17-related cytokines, IL-6 and IL-17A, showed gradual increases until day 42 PI. In conclusion, Th1, Th2, and Th17-related cytokine production might be important in immune responses against T. leonina VLM in experimental mice.
Animals ; Brain/parasitology ; Cytokines/*metabolism ; Female ; Gene Expression Regulation ; Heart/parasitology ; Interleukins/*metabolism ; Intestines/parasitology ; Larva Migrans, Visceral/*immunology/parasitology ; Liver/parasitology ; Lung/parasitology/pathology ; Mice ; Mice, Inbred C57BL ; Muscles/parasitology ; Spleen/parasitology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology ; Toxascaris/*immunology