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CMAJ : Canadian Medical Association... Jun 2024
Review
Topics: Humans; Food Hypersensitivity; Infant; Child, Preschool; Administration, Oral; Desensitization, Immunologic; Allergens
PubMed: 38885980
DOI: 10.1503/cmaj.231478 -
Cureus May 2024A 75-year-old woman, with hypertension and atrial fibrillation but no prior renal history, presented to the hospital for chest discomfort and dyspnea. She was found to...
A 75-year-old woman, with hypertension and atrial fibrillation but no prior renal history, presented to the hospital for chest discomfort and dyspnea. She was found to be in acute renal failure, with a serum creatinine of 5.1, increased from a baseline of 0.9, and urine analysis revealing proteinuria and hematuria with dysmorphic red blood cells. Subsequent work up was significant for positive perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and myeloperoxidase antibodies. She underwent a renal biopsy, which revealed necrotizing crescents in 12 of 14 glomeruli, and she was diagnosed with rapidly progressive glomerulonephritis due to microscopic polyangiitis. Despite aggressive treatment with plasmapheresis, high-dose prednisone, and rituximab infusions, renal function worsened, and she required initiation of hemodialysis. She was ultimately discharged after a three-week admission, with plans to continue rituximab infusions and three times weekly hemodialysis in the outpatient setting. Due to her poor response to traditional therapies, initiation of a new targeted immunomodulator known as avacopan, a complement 5a receptor antagonist, was considered. Such targeted immunomodulators are also of particular interest as possible ways to reduce the risk of severe infection associated with current broad immunosuppressive modalities. In addition, when used in place of steroids, they reduce the morbidity associated with cumulative glucocorticoid toxicity. For patients with ANCA-associated vasculitis refractory to standard therapies, targeted immunomodulators such as avacopan should be considered as alternative or adjunct therapy.
PubMed: 38883118
DOI: 10.7759/cureus.60366 -
Cureus May 2024Secondary organizing pneumonia (SOP) as a sequela to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually has a prolonged benign course with a good...
Secondary organizing pneumonia (SOP) as a sequela to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually has a prolonged benign course with a good response to corticosteroids. We present a case series of three patients who developed rapid progression to organizing pneumonia, after initial presentation with SARS-CoV-2. Imaging revealed rapid interval progression of bilateral subpleural ground glass opacities, and lung biopsy showed dense fibroblastic plugs within the alveoli. Two patients were steroid-responsive, and one patient succumbed to his illness despite maximal therapy. We postulate that B-cell depletion and immunosuppression may cause rapid progression to SOP, as all three patients were immunosuppressed and on chronic rituximab therapy.
PubMed: 38883063
DOI: 10.7759/cureus.60328 -
Cureus May 2024Histoplasmosis is a fungal infection caused by the fungus . It can manifest in various ways, ranging from pulmonary to disseminated presentations. Most of the...
Histoplasmosis is a fungal infection caused by the fungus . It can manifest in various ways, ranging from pulmonary to disseminated presentations. Most of the disseminated cases are seen in immunocompromised patients; here, we present an unusual case of an 81-year-old Mexican male with a history of cave exposure in his childhood, with 75 years of incubation period of the disease, who developed disseminated cutaneous histoplasmosis with no evident immunocompromising conditions. We considered the hypotheses of transient immunosuppression, CD4+ T lymphocytopenia, and immune senescence as the cause of this manifestation. The present case is also notable for its recurrence following therapy. This report underscores the challenges in diagnosing histoplasmosis in immunocompetent individuals and highlights the importance of long-term treatment and follow-up.
PubMed: 38883060
DOI: 10.7759/cureus.60433 -
Cureus May 2024Hemolytic uremic syndrome (HUS) is a prevalent cause of severe acute kidney injury in children, often leading to chronic renal damage. It is characterized by thrombotic...
Hemolytic uremic syndrome (HUS) is a prevalent cause of severe acute kidney injury in children, often leading to chronic renal damage. It is characterized by thrombotic microangiopathy (TMA), which represents a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. The choice of treatment and management strategies depends primarily on the underlying etiology. We present the case of a two-year-old girl diagnosed with rapidly progressive glomerulonephritis accompanied by hypertension necessitating renal replacement therapy. Initial laboratory findings indicated positive antinuclear antibodies, prompting immunosuppression and renal biopsy, revealing TMA with minimal chronicity changes. The treatment involved plasmapheresis and a single dose of injection rituximab, resulting in clinical recovery with an improved glomerular filtration rate. Since the anti-complement factor H antibody result was negative, the genetic etiology of atypical HUS was considered. The patient was discharged with favorable outcomes, including normal urine output and the absence of edema. This case concludes that young children with atypical HUS may present with a severe clinical course necessitating early intervention. The lack of genetic analysis facilities in severe cases should not hinder the timely initiation of plasmapheresis to prevent further injury and progression to chronic kidney disease.
PubMed: 38883005
DOI: 10.7759/cureus.60502 -
JHEP Reports : Innovation in Hepatology Jul 2024Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC)...
BACKGROUND & AIMS
Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy.
METHODS
M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using -generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models.
RESULTS
We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-β signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-β upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of significantly reduced ARG1S100A8/9 M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γGZMBCD8 T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs.
CONCLUSIONS
PPP1R15A M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies.
IMPACT AND IMPLICATIONS
Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.
PubMed: 38882672
DOI: 10.1016/j.jhepr.2024.101087 -
International Journal of Nanomedicine 2024This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have... (Review)
Review
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
Topics: Animals; Humans; Cytokines; Nanomedicine; Nanoparticles; Nanostructures; Stroke; T-Lymphocytes
PubMed: 38882535
DOI: 10.2147/IJN.S456632 -
Heliyon Jun 2024Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is...
Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured and . We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8IFNγ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.
PubMed: 38882349
DOI: 10.1016/j.heliyon.2024.e32260 -
JAAD International Jun 2024Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often...
BACKGROUND
Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant.
OBJECTIVES
To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP).
METHODS
Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed.
RESULTS
irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated levels and a possible role of phagosome signaling compared with LP.
LIMITATIONS
The study is descriptive and necessitates further investigation with larger cohorts and broader analyses.
CONCLUSION
irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression.
PubMed: 38882039
DOI: 10.1016/j.jdin.2023.11.013 -
Scientific Reports Jun 2024This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of...
Dual T-cell depletion with individually tailored anti-thymocyte globulin and attenuated dose of post-transplant cyclophosphamide in haploidentical peripheral stem cell transplantation.
This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.
Topics: Humans; Antilymphocyte Serum; Cyclophosphamide; Male; Female; Adult; Middle Aged; Graft vs Host Disease; Retrospective Studies; T-Lymphocytes; Lymphocyte Depletion; Transplantation, Haploidentical; Transplantation Conditioning; Young Adult; Peripheral Blood Stem Cell Transplantation; Adolescent; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Immunosuppressive Agents
PubMed: 38880835
DOI: 10.1038/s41598-024-64361-5