B cell-derived GABA elicits IL-10⁺ macrophages to limit anti-tumour immunity

GABAを標的とする抗腫瘍免疫機構 --代謝産物を介した免疫細胞間制御の一端を解明--. 京都大学プレスリリース. 2021-11-10.Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8⁺ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses

Different dorsal horn neurons responding to histamine and allergic itch stimuli

We examined whether different itch signals converge on the same dorsal horn neurons in mice. Intradermal injections of histamine and SLIGRL-NH2 (protease-activated receptor-2 agonist) induced scratching in naive mice and so did mosquito allergen in sensitized mice. These stimuli induced Fos expression in cells in the superficial dorsal horn. Fos-positive cells were mainly distributed within the isolectin B4-labeled region (inner aspect of lamina II) after histamine injection. In contrast, they were in the region dorsal to the isolectin B4-labeled region after injections of SLIGRL-NH2 and mosquito allergen. These results suggest that allergic itch signal is mediated by primary afferents expressing protease-activated receptor-2 and the neurons receiving signals of protease-associated itch and allergy-associated itch are different from those of histamine-induced itch

Different roles of capsaicin-sensitive and H-1 histamine receptor-expressing sensory neurones in itch of mosquito allergy in mice

Although mosquito allergy induces the release of histamine, the itch-related response, scratching, is not effectively suppressed by blockade of H, histamine receptors. To address this question, we examined the effects of neonatal capsaicin treatment on allergic reactions and H, histamine receptor-expressing sensory neurones in mice. Neonatal capsaicin treatment almost completely abolished allergy-associated scratching, without effects on plasma extravasation or increase in serum concentrations of immunoglobulins E and G,. An injection of edema contents from an animal exhibiting allergic reaction elicited scratching in naive animals, suggesting the production of pruritogen(s) by allergic reaction; this production was not suppressed by neonatal capsaicin treatment. This treatment markedly decreased the number of sensory neurones immunoreactive for TRPV1 capsaicin receptor, with little effect on sensor), neurones immunoreactive for neurofilament 200, a marker of myelinated A-fibre neurones. In addition, there was a trend towards a reduction in numbers of sensory neurones immunoreactive for H, histamine receptor. The results suggest that capsaicin-sensitive sensory neurones that lack H, histamine receptors play a key role in signalling of allergic itch

Consideration of Intestinal Failure in Cases of De-Adaptation of Short Bowel Syndrome: A Case Report and Descriptive Review

Short bowel syndrome (SBS) causes malabsorption due to extensive intestinal resection. While intestinal function declines with age, little is known about the relationship between intestinal failure and ageing. For the first time in Japan, we report a case of de-adaptation of SBS thought to be due to ageing, in a 93-year-old woman who presented with electrolyte imbalance and malnutrition. She had undergone five surgical resections of the small intestine over the past 20 years. She had developed SBS once due to multiple surgeries, but due to compensatory function, the symptoms had abated. However, due to decreased intestinal function caused by ageing, it worsened and symptoms reappeared. A literature search for the period January 1990 to May 2021 in Ichushi a major journal in Japan, found that de-adaptation of SBS occurred in 23 previous cases, of which we were able to confirm the details in 17 cases, with no case reports on “de-adaptation of SBS”, demonstrating that the concept of “intestinal failure” has only recently begun to be used in routine practice. Therefore, we stress the importance of re-emphasizing the concept of ”intestinal failure” in everyday practice, as well as other organ-related conditions such as cardiac or renal failure, as this may lead to a better understanding of the pathogenesis of malnutrition and diarrhoea in elderly patients

Efficacy of rituximab for the treatment and prevention of autoimmunity in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia

Immunological dysfunction in multiple lineages of hematopoietic cells and mixed chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of autoimmunity in patients with Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). Here, we report the efficacy of rituximab against autoimmunity in five patients with WAS and XLT. One patient with systemic arthritis and vasculitis, and two patients with immune thrombocytopenia were successfully treated with rituximab before initiating reduced-intensity conditioning. Rituximab was also used in combination with conditioning to prevent autoimmunity by depleting the recipient B cells in the other two patients with XLT. None of the patients developed autoimmunity without delay in donor B cell reconstitution, even though two patients had stable mixed chimerism after HSCT. These results suggest that aberrant B cell-intrinsic mechanisms are a central cause of autoimmunity, and rituximab is an effective therapeutic option for autoimmunity in patients with WAS and XLT

Possible Involvement of 5-Lipoxygenase Metabolite in Itch-Associated Response of Mosquito Allergy in Mice

This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B4 antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D4 antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, the H2 histamine-receptor antagonist cimetidine, the H1 histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT1/2 serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 µM) did not affect high K+-induced increase in intracellular Ca2+ concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B4 and cysteinyl leukotrienes are involved in mosquito allergy-associated itching

Effects of topical application of tacrolimus on acute itch-associated responses in mice

Using mice, we examined whether the topical application of tacrolimus would produce an acute anti-pruritic effect. An itch-related response, scratching, was elicited by intradermal injections of mosquito allergen (10 mu g/site) in sensitized mice and SLIGRL-NH2 (Protease-activated receptor-2 agonist, 50 nmol/site), histamine (100 nmol/site), serotonin (100 nmol/site) and substance P (100 nmol/site) in naive ones. Topical application of 1%, but neither 0.1% nor 0.3%, tacrolimus to the skin I h before injection inhibited scratching induced by mosquito allergen and SLIGRL-NH2, without effects on scratching induced by histamine, serotonin, and substance P. Topical tacrolimus also inhibited licking induced by an intraplantar injection of capsaicin (0.1 mu g/site). These results suggest that topical tacrolimus exerts acute inhibitory effects on allergic and protease-activated receptor-2-mediated itching. Though precise mechanisms remain unclear, the action on sensory neurons expressing protease-activated receptor-2 and transient receptor potential vanilloid-1 capsaicin receptor may be involved in the inhibitory effects of tacrolimus

A novel validated method for predicting the risk of re-hospitalization for worsening heart failure and the effectiveness of the diuretic upgrading therapy with tolvaptan.

Increased re-hospitalization due to acute decompensated heart failure (ADHF) is a modern issue in cardiology. The aim of this study was to investigate risk factors for re-hospitalization due to worsening heart failure, and the effect of tolvaptan (TLV) on decreasing the number of re-hospitalizations. This was a multicenter, retrospective study. The re-hospitalization factors for 1191 patients with ADHF were investigated; patients receiving continuous administration of TLV when they were discharged from the hospital (n = 194) were analyzed separately. Patients were classified into 5 risk groups based on their calculated Preventing Re-hospitalization with TOLvaptan (Pretol) score. The total number of patients re-hospitalized due to worsening heart failure up to one year after discharge from the hospital was 285 (23.9%). Age ≥80 years, duration since discharge from the hospital after previous heart failure 7.2 mg/dl, left ventricular ejection fraction (LVEF) 44.7 ml/m2, loop diuretic dose ≥20 mg/day, hematocrit <31.6%, and estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2 were independent risk factors for re-hospitalization for worsening heart failure. There was a significant reduction in the re-hospitalization rate among TLV treated patients in the Risk 3 group and above. In conclusions, age, duration since previous heart failure, diabetes mellitus, hemoglobin, uric acid, LVEF, LAVI, loop diuretic dose, hematocrit, and eGFR were all independent risk factors for re-hospitalization for worsening heart failure. Long-term administration of TLV significantly decreases the rate of re-hospitalization for worsening heart failure in patients with a Pretol score of 7