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Pediatric Nephrology (Berlin, Germany) Dec 2023The use of live attenuated vaccines in patients with immunosuppressive agents is contraindicated in package inserts and guidelines in Japan and other countries. However,... (Review)
Review
The use of live attenuated vaccines in patients with immunosuppressive agents is contraindicated in package inserts and guidelines in Japan and other countries. However, patients receiving immunosuppressants have a high risk of infectious disease becoming severe, and the necessity to prevent infectious disease is high. To date, 2,091 vaccinations have been reported in 25 reports of live attenuated vaccines in people receiving immunosuppressants. Twenty-three patients (1.1%) became infected with the virus strain used in the vaccine, which was varicella virus in 21 patients. No reports have described life-threatening complications. A prospective study at the National Center for Child Health and Development conducted under certain immunological conditions (CD4 cell count ≥ 500/mm, stimulation index of lymphocyte blast transformation by phytohemagglutinin (PHA) ≥ 101.6, serum immunoglobulin G ≥ 300 mg/dL) confirmed the serological effectiveness and safety. The evidence suggests that live attenuated vaccines can be used even in combination with immunosuppressants. Further evidence must be gathered and immunological criteria investigated to determine the conditions for safe use. Depending on the results of these investigations, the wording in package inserts and guidelines may need to be revised.
Topics: Child; Humans; Immunosuppressive Agents; Vaccines, Attenuated; Prospective Studies; Immune System Diseases; Communicable Diseases
PubMed: 37076756
DOI: 10.1007/s00467-023-05969-z -
The Journal of Experimental Medicine Jan 2024Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous...
Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.
Topics: Infant; Humans; Animals; Mice; CD28 Antigens; CD4-Positive T-Lymphocytes; Immunologic Deficiency Syndromes; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Receptors, Antigen, T-Cell; Inflammation; Lymphopenia
PubMed: 37962568
DOI: 10.1084/jem.20230927 -
Stem Cell Research & Therapy Apr 2024Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex...
BACKGROUND
Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex cryopreservation is a good choice to preserve female fertility before cancer treatment. Following the remission of the disease, the thawed ovarian tissue can be transplanted back and restore fertility of the patient. However, there is a risk to reintroduce cancer cells in the body and leads to the recurrence of cancer. Given the low success rate of current in vitro culture techniques for obtaining mature oocytes from primordial follicles, an artificial ovary with primordial follicles may be a good way to solve this problem.
METHODS
In the study, we established an artificial ovary model based on the participation of mesenchymal stem cells (MSCs) to evaluate the effect of MSCs on follicular development and oocyte maturation. P2.5 mouse ovaries were digested into single cell suspensions and mixed with bone marrow derived mesenchymal stem cells (BM-MSCs) at a 1:1 ratio. The reconstituted ovarian model was then generated by using phytohemagglutinin. The phenotype and mechanism studies were explored by follicle counting, immunohistochemistry, immunofluorescence, in vitro maturation (IVM), in vitro fertilization (IVF), real-time quantitative polymerase chain reaction (RT-PCR), and Terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL) assay.
RESULTS
Our study found that the addition of BM-MSCs to the reconstituted ovary can enhance the survival of oocytes and promote the growth and development of follicles. After transplanting the reconstituted ovaries under kidney capsules of the recipient mice, we observed normal folliculogenesis and oocyte maturation. Interestingly, we found that BM-MSCs did not contribute to the formation of follicles in ovarian aggregation, nor did they undergo proliferation during follicle growth. Instead, the cells were found to be located around growing follicles in the reconstituted ovary. When theca cells were labeled with CYP17a1, we found some overlapped staining with green fluorescent protein(GFP)-labeled BM-MSCs. The results suggest that BM-MSCs may participate in directing the differentiation of theca layer in the reconstituted ovary.
CONCLUSIONS
The presence of BM-MSCs in the artificial ovary was found to promote the survival of ovarian cells, as well as facilitate follicle formation and development. Since the cells didn't proliferate in the reconstituted ovary, this discovery suggests a potential new and safe method for the application of MSCs in clinical fertility preservation by enhancing the success rate of cryo-thawed ovarian tissues after transplantation.
Topics: Female; Animals; Mesenchymal Stem Cells; Mice; Ovary; Oocytes; Mesenchymal Stem Cell Transplantation; Ovarian Follicle
PubMed: 38650029
DOI: 10.1186/s13287-024-03718-z -
Frontiers in Immunology 2023Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure...
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Topics: Humans; HIV Infections; HIV-1; Virus Activation; Virus Latency; Alendronate; HIV Seropositivity
PubMed: 37744358
DOI: 10.3389/fimmu.2023.1219250 -
Asia Pacific Allergy Dec 2023White bean allergy is uncommon and rarely reported. Herein, we report a case of white bean allergy in a patient with Down syndrome. A 7-year-old girl with Down syndrome...
White bean allergy is uncommon and rarely reported. Herein, we report a case of white bean allergy in a patient with Down syndrome. A 7-year-old girl with Down syndrome experienced allergic symptoms twice after eating white bean and visited our hospital for a food allergy investigation. An ImmunoCAP assay revealed a white bean-specific IgE (13.4 kU/L) in the patient's serum. In addition, her skin prick test result was positive. Moreover, ingestion of 2 g of boiled white beans in an oral food challenge test induced intermittent cough, desaturation, generalized urticaria, abnormal sleep, and mild hypotension. Thus, we diagnosed the patient with white bean allergy. We performed western blotting and mass spectrometric analysis and detected the following allergens: Phytohemagglutinin, group 3 late embryogenesis abundant protein, lipoxygenase, and legumin. In addition, we detected several candidate allergenic proteins for the first time. White bean, runner bean, or azuki bean was considered the primary source of sensitization because although immunoblotting inhibition tests revealed that the abovementioned beans inhibited other legumes, soybean, which she tolerates, showed little inhibition of the other legumes. However, we could not confirm whether the patient could ingest legumes other than soybean or white bean because her family did not wish to continue with further testing. This is the first report of a case of systemic allergic reactions to white bean in a child with Down syndrome. Further studies are needed to identify white bean allergens and understand the relationship between Down syndrome and white bean allergy.
PubMed: 38094097
DOI: 10.5415/apallergy.0000000000000111 -
European Journal of Medicinal Chemistry Nov 2023Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca...
Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca homeostasis. Here, we present the structure-activity relationship, K1.3 inhibition, and immunosuppressive effects of new thiophene-based K1.3 inhibitors with nanomolar potency on K current in T-lymphocytes and K1.3 inhibition on Ltk cells. The new K1.3 inhibitor trans-18 inhibited K1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC value of 26.1 nM and in mammalian Ltk cells with an IC value of 230 nM. The K1.3 inhibitor trans-18 also had nanomolar potency against K1.3 in Xenopus laevis oocytes (IC = 136 nM). The novel thiophene-based K1.3 inhibitors impaired intracellular Ca signaling as well as T-cell activation, proliferation, and colony formation.
Topics: Animals; Mammals; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Structure-Activity Relationship; T-Lymphocytes; Thiophenes; Immunosuppressive Agents
PubMed: 37454520
DOI: 10.1016/j.ejmech.2023.115561 -
General and Comparative Endocrinology Jul 2023Steroid hormones (e.g. androgens [AN] and corticosterone [CORT]) modulate complex physiological functions such as reproduction, energy mobilization, metabolism, and...
Steroid hormones (e.g. androgens [AN] and corticosterone [CORT]) modulate complex physiological functions such as reproduction, energy mobilization, metabolism, and immunity. The effects of these steroids on immunocompetence and its metabolic costs can also be affected by fluctuations in environmental resource availability and other factors such as parasitism. To understand these possible interactions, we studied AN and CORT, immune response [swelling response to phytohemagglutinin (PHA) injection and bacterial killing ability (BKA)], parasite load, resting metabolic rate (RMR) and post-immune challenge (PHA injection) oxygen consumption rates during two different phases of the annual cycle of Rhinella jimi toads from the Brazilian semi-arid region (Caatinga), where environmental conditions are highly seasonal. We observed an increase in O consumption rates after both PHA and saline (control) injections, indicating a metabolic response to adverse stimuli rather than the immune challenge. Toads showing higher RMR and VO after the adverse stimuli (PHA/saline injections) had lower field AN and CORT plasma levels, suggesting these hormones might mediate a metabolic energy conservation strategy both at baseline levels and after adverse stimuli. Parasite load appear to constrain the metabolic response to PHA and saline injections. Additionally, individuals with a higher swelling response to PHA had higher field CORT plasma levels (particularly when males are breeding), which opposes the idea of a possible trade-off between reproductive activity and other physiological traits, indicating the immunoenhancing effects of elevated CORT at physiological levels. BKA did not show a seasonal variation or correlation with body condition or hormone levels, indicating that the immune surveillance mediated by the complement remains constant despite ecological and physiological changes.
Topics: Humans; Male; Animals; Bufonidae; Androgens; Seasons; Steroids; Immunity; Corticosterone
PubMed: 36931441
DOI: 10.1016/j.ygcen.2023.114263 -
Biomolecules Jul 2023Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light... (Review)
Review
Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/- mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.
Topics: Female; Male; Humans; Animals; Mice; HLA-B27 Antigen; HLA Antigens; Cell Membrane; Cytokines; Anti-Bacterial Agents; Antibodies, Monoclonal
PubMed: 37627243
DOI: 10.3390/biom13081178 -
International Immunopharmacology Jul 2023Leukocyte phytohemagglutinin (PHA-L) is a tetrameric isomer of phytohemagglutinin (PHA) purified from the red kidney bean (Phaseolus vulgaris) and is a well-known human...
Recombinant Phaseolus vulgaris phytohemagglutinin L-form expressed in the Bacillus brevis exerts in vitro and in vivo anti-tumor activity through potentiation of apoptosis and immunomodulation.
Leukocyte phytohemagglutinin (PHA-L) is a tetrameric isomer of phytohemagglutinin (PHA) purified from the red kidney bean (Phaseolus vulgaris) and is a well-known human lymphocyte mitogen. Due to its antitumor and immunomodulatory effects, PHA-L may serve as a potential antineoplastic agent in future cancer therapeutics. However, various negative consequences of PHA have been reported in the literature as a result of the restricted acquisition methods, including oral toxicity, hemagglutinating activity, and immunogenicity. There is a critical need to explore a new method to obtain PHA-L with high purity, high activity and low toxicity. In this report active recombinant PHA-L protein was successfully prepared by Bacillus brevius expression system, and the antitumor and immunomodulatory activities of recombinant PHA-L were characterized by in vitro and in vivo experiments. The results showed that recombinant PHA-L protein had stronger antitumor effect, and its anti-tumor mechanism was realized through direct cytotoxicity and immune regulation. Importantly, compared with natural PHA-L, the recombinant PHA-L protein showed the lower erythrocyte agglutination toxicity in vitro and immunogenicity in mice. Altogether, our study provides a new strategy and important experimental basis for the development of drugs with dual effects of immune regulation and direct antitumor activity.
Topics: Humans; Animals; Mice; Phytohemagglutinins; Phaseolus; Bacillus; Recombinant Proteins; Neoplasms; Apoptosis
PubMed: 37269742
DOI: 10.1016/j.intimp.2023.110322 -
Conservation Physiology 2023Infectious diseases are a major driver of the global amphibian decline. In addition, many factors, including genetics, stress, pollution, and climate change can...
Infectious diseases are a major driver of the global amphibian decline. In addition, many factors, including genetics, stress, pollution, and climate change can influence the response to pathogens. Therefore, it is important to be able to evaluate amphibian immunity in the laboratory and in the field. The phytohemagglutinin (PHA) assay is an inexpensive and relatively non-invasive tool that has been used extensively to assess immunocompetence, especially in birds, and more recently in amphibians. However, there is substantial variation in experimental methodology among amphibian PHA studies in terms of species and life stages, PHA doses and injection sites, and use of experimental controls. Here, we compile and compare all known PHA studies in amphibians to identify knowledge gaps and develop best practices for future work. We found that research has only been conducted on a limited number of species, which may not reflect the diversity of amphibians. There is also a lack of validation studies in most species, so that doses and timing of PHA injection and subsequent swelling measurements may not effectively evaluate immunocompetence. Based on these and other findings, we put forward a set of recommendations to make future PHA studies more consistent and improve the ability to utilize this assay in wild populations, where immune surveillance is greatly needed.
PubMed: 38090122
DOI: 10.1093/conphys/coad090