Search

Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive [CD8.sup.*] T cells into exhausted/regulatory ones, through an IFN-[gamma]-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection., Not all transplanted organs are created equal Kidney and liver allografts are capable of actively contributing to the induction and maintenance of immunological tolerance (1, 2), while heart and lung [...]

Purpose We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients. Methods In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 [micro]g every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients. Results The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41-66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94-3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment. Conclusions Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment., Author(s): Antoine Roquilly [sup.1] [sup.2], Bruno Francois [sup.3], Olivier Huet [sup.4], Yoann Launey [sup.5], Sigismond Lasocki [sup.6], Emmanuel Weiss [sup.7], Melanie Petrier [sup.2], Yannick Hourmant [sup.1], Marwan Bouras [sup.1] [sup.2], [...]

BACKGROUND: Maternal factors are implicated in the onset of childhood asthma. Differentiation of naive CD4+ T lymphocytes into pro-allergic T-helper 2 cells induces interleukin (IL)4 expression and inhibits interferon (IFN)[gamma] [...]

Malaria-induced sepsis is associated with an intense proinflammatory cytokinemia for which the underlying mechanisms are poorly understood. It has been demonstrated that experimental infection of humans with Plasmodium falciparum primes Toll-like receptor (TLR)-mediated proinflammatory responses. Nevertheless, the relevance of this phenomenon during natural infection and, more importantly, the mechanisms by which malaria mediates TLR hyperresponsiveness are unclear. Here we show that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes involving TLR signaling, had sites for IFN-inducible transcription factors. To further define the mechanism involved in malaria-mediated 'priming,' we infected mice with Plasmodium chabaudi. The human data were remarkably predictive of what we observed in the rodent malaria model. Malaria-induced priming of TLR responses correlated with increased expression of TLR mRNA in a [TLR9.sup.-/-], MyD88-, and IFN[gamma]-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while [TLR9.sup.-/-], [IL12.sup.-/-] and to a greater extent, [IFN[gamma].sup.-/-] mice were protected, Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFN[gamma], responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.

When compared with normal milk, bovine colostrum contains a large amount of uridine 5'-monophosphate (UMP) and its derivatives. In the present study, we carried out 2 experiments to determine the effects of dietary UMP (2 g/d) on the immune status of newborn calves. In Exp. 1, newborn Holstein bull calves were fed milk replacer alone (control group) or milk replacer supplemented with UMP (UMP group) from d 4 to 10 after birth. The increase in interferon-[gamma] concentration by peripheral blood mononuclear cells (PBMC) on d 24 tended to be greater in the UMP group than in the control group (P = 0.06). The IgA concentration of the ileal mucosa was greater in the UMP group than in the control group (P < 0.05), although there was no difference between groups in the jejunal mucosa. In Exp. 2, newborn Holstein bull calves were fed milk replacer alone (control group) or milk replacer supplemented with UMP (UMP group) from d 4 to 56 after birth. The proliferation of PBMC was greater in the UMP group than in the control group on d 14, 28, and 42 (P < 0.01). The increase in interferon-[gamma] concentration by PBMC was greater in the UMP group than in the control group on d 28 and 42 (P < 0.05). From these results, we concluded that dietary UMP affected the immune responses of newborn calves. Key words: interferon-[gamma] mucosal immunoglobulin A, peripheral blood mononuclear cell proliferation, uridine 5'-monophosphate

Cytotoxic lymphocyte antigen-4 (CTLA-4) blockade is an active immunotherapeutic strategy that is currently in clinical trials in cancer. There are several ongoing trials of anti-CTLA-4 in the metastatic setting of prostate cancer patients with reported clinical responses consisting of decreases in the prostate specific antigen (PSA) tumor marker for some patients. Immunologic markers that correlate with these clinical responses are necessary to guide further development of anti-CTLA-4 therapy in the treatment of cancer patients. We recently reported that [CD4.sup.+] inducible co-stimulator [(ICOS).sup.hi] T cells that produce interferon-[gamma] (IFN-[gamma]) are increased in the peripheral blood and tumor tissues of bladder cancer patients treated with anti-CTLA-4 antibody. Here we present data from the same clinical trial in bladder cancer patients demonstrating a higher frequency of [CD4.sup.+][ICOS.sup.hi] T cells and IFN-[gamma] mRNA levels in nonmalignant prostate tissues and incidental prostate tumor tissues removed at the time of radical cystoprostatectomy. Our data suggest immunologic markers that can be used to monitor prostate cancer patients who receive anti-CTLA-4 therapy and indicate that the immunologic impact of anti-CTLA-4 antibody can occur in both tumor and nonmalignant tissues. These data should be taken into consideration for evaluation of efficacy as well as immune-related adverse events associated with anti-CTLA-4 therapy. clinical trial | CTLA-4 | T cells

The CD8 co-receptor can modulate CD[8.sup.+] T cell function through its contributions to T cell receptor (TCR) binding and signaling. Here we show that IFN-[gamma] and IL-4 exert opposing effects on the expression of CD8[alpha] mRNA and surface CD8 protein during CD[8.sup.+] T cell activation. IL-4 caused down-regulation of surface CD8 on ovalbumin [(OVA).sub.257-264]-specific TCR-otransgenic OT-I CD[8.sup.+] T cells activated with [OVA.sub.257-264]-coated antigen presenting cells or polyclonal stimuli, and on wild type CD[8.sup.+] T cells activated with polyclonal stimuli. This effect was enhanced in each case when the cells lacked a functional IFN-[gamma] or IFN-[gamma]R gene. When WT or IFN-[gamma]-deficient OT-I CD[8.sup.+] T cells were analyzed 9 days after co-injection with control or IL-4-expressing [OVA.sup.+] tumor cells into RAG-[2.sup.-/-][gamma][c.sup.-/-] mice, CD8 levels were highest on WT donor cells from mice that received the control tumor and lowest on IFN-[gamma]-deficient donor cells from mice that received the IL-4-expressing tumor. The latter CD[8.sup.low] cells displayed markedly impaired binding of [OVA.sub.257-264]/MHC tetramers and peptide/MHC-dependent degranulation. The data reveal an unexpected role for IFN-[gamma] in tuning the CD8 co-receptor during primary CD[8.sup.+] T cell activation both in vitro and in vivo. CD8low | co-receptor tuning | T cell activation | cytotoxic T lymphocytes | cytokines

The objective of this study was to determine the effect of carprofen (C) administration before banding or burdizzo castration of bulls on cortisol, in vitro interferon-[gamma] (IFN-[gamma]) production, acute-phase proteins, feed intake, and growth. Fifty Holstein Friesian bulls (5.5 mo old; 191 [+ or -] 3.7 kg) were blocked by weight and assigned randomly to 1 of 5 treatments (n = 10/ treatment): 1) untreated control (2) banding castration at 0 min (Band); 3) Band following an i.v. injection of 1.4 mg/kg of BW of C at -20 min (Band+C); 4) Burdizzo castration at 0 min (Burd); or 5) Burd following 1.4 mg/ kg of BW of C at -20 min (Burd+C). Castration acutely increased plasma cortisol concentrations compared with control; no significant differences occurred in peak and interval to peak cortisol responses between Band and Band+C or Burd and Burd+C groups. The administration of C in Band+C reduced (P < 0.05) the cortisol concentration between 6 and 12 h postcastration compared with Band animals. Overall, the integrated cortisol response was greater (P < 0.05) in the castrates than in control, whereas C treatments tended to reduce this response compared with Band (P = 0.08) and Burd (P = 0.07), respectively. Plasma fibrinogen was elevated in Band animals on d 14 and in Burd animals on d 3 and 14. Carprofen administration reduced Band- and Burd-induced fibrinogen production on d 14 and 3, respectively. Plasma haptoglobin was elevated in Band animals on d 3 and 35 compared with control, and C adminstration was effective in reducing the haptoglobin elevation on d 35 in Band+C compared with Band. There were no differences among treatments in in vitro IFN-[gamma], production induced by concanavalin A and phytohemagglutinin on d 1 and 2. Overall from d-1 to 16, there were no DMI differences among treatments. From d-1 to 35, there were no ADG differences among treatments. In conclusion, banding and burdizzo castration increased plasma cortisol with no change in in vitro IFN-[gamma] production. Carprofen (1.4 mg/kg of BW) tended to reduce the integrated cortisol response, and it reduced cortisol secretion in banded animals between 6 and 12 h postcastration. There was an increased acute-phase protein production following castration; this response was effectively moderated by the administration of C before castration. Key words: acute-phase protein, carprofen, castration, cattle, interferon-[gamma], stress

Interferon gamma does not appear to benefit patients with a serious lung disease called idiopathic pulmonary fibrosis, according to a study of 330 patients. After one year of treatment, symptoms, quality of life, and lung function were similar in patients who took interferon gamma and those who took a placebo, or inactive substance. Interferon gamma is a natural substance in the body that is believed to be deficient in patients with this lung disease.

Giving HIV patients highly active antiretroviral therapy (HAART), interleukin, and gamma-interferon inhibits viral reproduction and boosts the immune system but does not necessarily completely eliminate the virus from the body. This was the conclusion of a study of 10 HIV patients who received this aggressive treatment.

Combining corticosteroids with interferon gamma-1b may be more beneficial than corticosteroids alone in patients with pulmonary fibrosis. Pulmonary fibrosis is a lung disease. Researchers randomly assigned 18 people with pulmonary fibrosis to take prednisolone only or prednisolone and interferon gamma-1b for one year. Patients who received both drugs experienced an improvement in lung function but those who received only prednisolone had a decline in lung function. Interferon gamma-1b caused fever, chills, and muscle pain, but these side effects did not last longer than a few months.

Rickettsia prowazekii, the bacterium that causes epidemic typhus, mainly grows within endothelial cells and can also infect macrophages. Previous studies showed that pretreatment of cultured, murine macrophage-like RAW264.7 cells with gamma interferon, followed by R. prowazekii infection, leads to the death of many of the macrophages within several hours after infection. The present study examined the fate of the rickettsiae after macrophage death. Rickettsiae released from gamma interferon-pretreated, infected macrophage cultures, in which 83 ± 4% (mean ± standard deviation) of the macrophages were trypan blue-positive (dead), remained viable, as judged by their ability to infect and grow in untreated Vero cells (originally established from the kidney of an African green monkey). The growth of these rickettsiae was comparable to the growth of rickettsiae released from untreated, infected macrophage cultures, in which 1 ± 1% of the macrophages were trypan blue-positive. These data raise the possibility that gamma interferon, which is known to be an anti-rickettsial host defense, may, in some instances, contribute to the spread of R. prowazekii infection within a host. Keywords: rickettsia, interferon, macrophage, INTRODUCTION Rickettsia prowazekii, an obligate intracellular bacterium and the cause of louse-borne epidemic typhus in humans, multiplies within the cytoplasm of its host cells. It grows mainly in the microvascular [...]