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PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗
PubMed2005

Cytokine profile in response to Cytomegalovirus associated with immune recovery syndrome after highly active antiretroviral therapy.

BACKGROUND: Several changes have occurred in the presentation and course of cytomegalovirus (CMV) retinitis in patients with AIDS since the introduction of HAART (highly active antiretroviral therapy). In some individuals who take HAART, retinitis is kept under control even after the discontinuation of anti-CMV therapy. However, many of these patients develop intraocular inflammation. Uveitis, cataract, vitreitis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with immune recovery syndrome (IRS). METHODS: We evaluated the CMV-specific immune response in 55 patients by assessing CMV-specific lymphocyte proliferation, cytotoxicity, and cytokine production and correlated it with the clinical outcome. RESULTS: Our data suggest that control of CMV retinitis is associated with acquisition of cytotoxic and lymphoproliferative responses to CMV. In addition, the upsurge of macular and disc edema seems associated with the production of interleukin-4 and tumor necrosis factor-alpha, whereas vitreitis is associated with the production of interleukin-2 and interferon-gamma. INTERPRETATION: The type of T-cell response that develops after HAART may determine the side effects of immune recovery and these effects are predictable based on the lymphokine profile produced by CMV-specific cells.

AIDS-Related Opportunistic Infections↗
PubMed2005

Expression profiling and validation of reference gene candidates in immune relevant tissues and cells from Atlantic salmon (Salmo salar L.).

The expression levels of three commonly used housekeeping genes, EF1-alpha, RPS20 and Beta-Actin, were examined in seven different tissues and leucocytes from non-stimulated Atlantic salmon (Salmo salar L.). The tissues analysed by quantitative real-time PCR were gill, liver, intestine, muscle, spleen, head kidney leucocytes (HKL) and peripheral blood leucocytes (PBL). The experiments were performed to investigate the transcriptional stability within and between tissues and leucocytes and between individuals. For all tissues and leucocytes, an appropriate reference gene was identified except for muscle tissue. HKL were used as a calibrator and the expression of EF1-alpha varied maximally 2.5-fold in five out of the six tissues and leucocytes investigated relative to the expression of 18S rRNA. The RPS20 gene was more intermediate and varied at least by a factor of two and maximally by a 20-fold factor. Beta-Actin was generally the most regulated gene showing high variations for gill (5.8x) and spleen tissue (10.3x) relative to the calibrator. A suitable reference gene for muscle tissue was not found since the expression varied between 8.3- and 25-fold for the three genes compared to the calibrator. By comparing the expression results of the non-stimulated tissues and leucocytes using the Normfinder programme, it was further shown that EF1-alpha was the most stably expressed gene both between individuals and the different tissues/leucocytes. Stimulation with lipopolysaccharide (LPS) of TO cells and HKL from Atlantic salmon was additionally performed to reveal whether an immune stimulating agent would change the expression level of EF1-alpha, RPS20 and Beta-Actin. LPS stimulation of cells revealed that RPS20 and EF1-alpha were least regulated by the LPS treatment in the TO cells relative to 18S rRNA, but in HKL, Beta-Actin was the most appropriate gene. However, the variations were overall maximally two-fold in LPS-stimulated TO cells and HKL, which make all three genes suitable as reference genes in this case. A further experiment showed that no RT- and/or PCR inhibitors were present in the non-stimulated tissues and cells, indicating true transcriptional differences.

Actins↗
PubMed1993

Babesia bovis-specific CD4+ T cell clones from immune cattle express either the Th0 or Th1 profile of cytokines.

The central role of T cells in the immune response against hemoprotozoan parasites, both as helper cells for T-dependent antibody production, and as effector cells acting directly or indirectly on intracellular parasites through the elaboration of cytokines, has prompted us to investigate the bovine cellular immune response against B. bovis antigens. T cell clones generated from four B. bovis-immune cattle by in vitro stimulation with soluble or membrane associated merozoite antigen were characterized for reactivity against various forms of antigen and different geographical isolates of B. bovis and B. bigemina. The clones were categorized into seven different groups based on differential patterns of reactivity. This panel of T cell clones and additional clones specific for either the 77 kDa merozoite apical complex associated protein (Bb-1) or the 42 kDa major merozoite protein (MSA-1) were analyzed for cytokines. Biological assays to measure IL-2/IL-4, IFN-gamma and TNF-alpha/TNF-beta and Northern blot analysis to detect mRNA encoding bovine IL2, IL-4, IFN-gamma, TNF-beta and TNF-alpha revealed the differential production of cytokines by clones with different antigen specificities. Two Bb-1-specific T cell clones produced the Th1 pattern of cytokines: IL-2, IFN-gamma, TNF-beta and TNF-alpha, but not IL-4. Clones specific for the 42 kDa protein produced undetectable levels of all cytokines, but expressed an unrestricted or Th0 pattern of cytokine mRNA: IL-2, IL-4, IFN-gamma and TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

The effect of different psychological profiles and timings of stress exposure on humoral immune response.

The aim of this study was to analyse the effects of different timings of stress exposure on humoral immune response in mice previously distinguished by their own psychological profile. The Swiss mice were submitted to two different protocols of social confrontation, based on the timing of stress exposure in relation to an immune challenge: animals socially confronted daily for 2 weeks (SINT) and another group confronted daily for 3 weeks (LINT). Control groups were individually housed in a different room. All groups were intraperitoneally injected with sheep red blood cells (SRBC). The SINT group was challenged on the 1st and 7th days of confrontation, whereas the LINT group was challenged on the 7th and 14th days. Two days prior to the period of social conflict, the animals were tested in the elevated plus-maze (PM). The SINT protocol caused a more depressed primary immune response in the submissive mice than that observed in the dominants. The LINT protocol induced a marked increase in the primary immune response, which was more evident in the dominant mice, whilst no changes were observed in the secondary immune response. In the control and dominant groups, the correlation analysis attributed a higher anti-SRBC titre to the more anxious animals; by contrast, higher anti-SRBC titres were found in the less anxious submissive mice. These studies show that different physiological and behavioural adaptations to environmental demands over time, as well as different psychological profiles, constitute important factors to a better understanding of neuro-immune interactions.

Adaptation, Psychological↗
PubMed1997

A malariometric survey in a rural community in the Muheza district, Tanzania: age profiles in the development of humoral immune responses.

A malariometric survey was carried out in a rural community situated in a malaria holoendemic endemic area of Tanzania. A random sample (n = 228) of different age groups was taken to elucidate the association between anti-Pf155/RESA and anti-Pf332 antibody responses and classical malaria indices. Parasitaemia, fever, splenomegaly, haematocrit and antimalarial consumption were assessed. Antibody responses against Pf155/RESA and Pf332 peptides were determined by ELISA. The age profiles of parasite density, splenomegaly, fever, haematocrit values and prevalence of antibody responses indicated intensive malaria exposure and the highest impact of malaria in small children. Forty-five percent of the study population had detectable chloroquine and desethyl-chloroquine blood levels, and the highest frequency and concentrations were recorded in the 12-23 months old. There was no significant association between the presence of drug and parasite density in the different age groups, although in the < 15 years old there was lower parasite prevalence among the children positive for drug in their blood (P < 0.05). High prevalence of antibody responses to all antigens was observed already at an early age, but the mean anti-Pf155/RESA and anti-Pf332 antibody levels increased significantly only in the adult group (P < 0.01). Significantly lower mean parasite densities were observed in high responders to Pf155/RESA and Pf332 peptides for the > or = 10 years old. For the 1-9 years, a similar difference was only observed in the high responders to Pf332. For the whole material, anti-Pf155/RESA and anti-Pf332 antibody levels correlated positively with age. When the effect of age was allowed for in analysing the relationship between parasite density and antibody level against the different antigens, a significant negative correlation was found only with regard to Pf332 in the > = 10 years age group. These results suggest that anti-Pf332 antibodies appear to be a better indicator for antiparasitic immunity, but both antigens are important for immune protection.

Adolescent↗
PubMed1997

The spleen, IgG antibody subsets and immunity to Plasmodium berghei in rats.

The development of IgG subclass-specific antibody responses to Plasmodium berghei in spleen-chimeric rats were monitored to determine if there was any relationship between IgG subset profiles and resistance. Strongly immune eusplenic rats respond to challenge with P. berghei by producing high levels of parasite-specific IgG2a, IgG2b and IgG2c but only modest levels of IgG1. Splenectomy profoundly affects the antibody response to infection. Thus, in splenectomized immunized rats, which harbour a chronic parasitaemia of 1%, the IgG2a, IgG2b and IgG2c responses peak 1 week later than in eusplenic immunized rats although the size of the peak is similar. More marked effects are apparent in the IgG1 response, the magnitude of which is far greater in splenectomized immunized rats than eusplenic immunized rats. Similar antibody profiles are seen in splenectomized immunized rats transplanted with a naive spleen. In contrast, splenectomized naive rats receiving either a transplant of a spleen from an immune rat or a transfer of immune spleen cells have high levels of IgG2a, IgG2b and IgG2c but modest levels of IgG1. However, only the former group of rats completely clears the parasite, the latter maintaining a chronic 1% parasitaemia. Thus, although complete resistance to P. berghei is always associated with high levels of parasite-specific IgG2a, IgG2b and IgG2c plus modest levels of IgG1, this is not a sufficient set of conditions to guarantee complete immunity. The IgG subset profile may be related to cytokine production; IFN-gamma was detected in the sera of rats receiving spleens from rats immune to P. berghei (modest IgG1 responses) but not in rats receiving spleens from naive animals (pronounced IgG1 responses).

Adoptive Transfer↗
PubMed2026

Multiomics profiling of plasma reveals lipid-immune dysregulation and exosome remodeling in mpox and mpox-HIV co-infection.

BACKGROUND: Monkeypox virus (MPXV) infects diverse human cell types, and human immunodeficiency virus (HIV) co-infection is common. The immunometabolic consequences of MPXV infection, and how it may be altered by HIV, remain poorly defined. METHODS: We performed quantitative plasma lipidomics and precise metabolomics in a discovery cohort (n = 81) comprising MPXV-monoinfected (MPLWOH), MPXV-HIV-coinfected (MPLWH), and HIV-monoinfected (PLWH) patients and healthy controls, integrating exosome proteomics, cytokine profiling, and transcriptomics of exosome-treated HepG2 and A549 cells for functional interpretation. An independent validation cohort (n = 65) was used to assess cross-cohort reproducibility. FINDINGS: MPXV infection induced broad lipid remodeling, with elevations in phosphatidylserine (PS) and phosphatidylethanolamine (PE) and reductions in phosphatidylcholine (PC), lysophospholipids, cholesteryl ester (CE), and exosomal lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL). These lipid alterations were correlated with tissue injury markers and inflammatory cytokines. The MPLWH group exhibited more severe metabolic disruption, including marked sulfatide (SL) depletion, lower cholesterol and high-density lipoprotein cholesterol (HDL-c), and extensive rewiring of lipid-cytokine associations. SL depletion in MPLWH correlated with abundances of COPI-mediated retrograde trafficking proteins in exosomes. Transcriptomic profiling of exosome-treated cells provided functional validation: MPLWOH exosomes induced lipid metabolism and repair-associated epithelial programs, while MPLWH exosomes drove phospholipid remodeling and acute inflammatory and mucosal barrier-stress responses. CONCLUSIONS: MPXV infection reprograms host lipid metabolism and exosome composition, with HIV co-infection amplifying inflammatory, metabolic, and trafficking disruptions. These convergent multi-omics signatures link systemic lipid dysregulation to exosome-mediated immunomodulation and identify potential targets for host-directed interventions. FUNDING: This study was funded by the Major Project of Guangzhou National Laboratory.

Adult↗
PubMed1997

Kinetics, localization and cytokine profile of T cell responses to immune stimulating complexes (iscoms) containing human influenza virus envelope glycoproteins.

Immune stimulating complexes (iscoms) are 40 nm particles combining adjuvant-active Quillaja saponins and multimeric presentation of antigens. The distribution in mice of influenza virus iscoms and the resulting T cell responses in the lymph nodes (LN) and spleen were characterized. After a single subcutaneous injection, iscoms were delivered to the draining LN where they induced a transient population of LN cells which responded with proliferation and secretion of interleukin-2 (IL-2), gamma-interferon (IFN-gamma) and interleukin-4 (IL-4) after restimulation. The response in the spleen developed more slowly, sustained for 12 weeks and was characterized by cells producing in particular IL-2 and IFN-gamma but also IL-4. A booster resulted in a dramatic enhancement of the production of IFN-gamma, indicating that iscoms efficiently recruit cells with Th1 properties. Comparisons of T cell responses to iscoms and to influenza virus antigen in Freund's complete adjuvant demonstrate that these adjuvants affect both the localization and cytokine profile of T cell responses.

Animals↗
PubMedDate not supplied

[Immune sexual dimorphism: can sex steroids affect the Th1/Th2 cytokine profile?].

Cytokine secretion is a crucial aspect in immune system modulation. The secretion pattern of these molecules determines the immune response type that will confront a particular antigen, and this pattern can be at least of two types. A Th1 pattern, effective to eliminate mainly intracellular pathogens and a Th2 pattern, crucial to eradicate extra cellular pathogens. There are many immunological factors that affect expression of these proteins and auto regulate the Th1/Th2 balance, but there are few evidences about effect of other protagonists of mammals physiology. This review focuses on the regulation of the Th1/Th2 cytokine secretion pattern of immune cells by sexual steroids. The evidences indicate that cytokines and steroids form a common chemical language effective to keep the balance between immune and endocrine systems. Alterations of this delicate network can explain different pathologies where gender-associated differences exist and where sexual steroids are crucial factors.

Cytokines↗
PubMed1982

Host defense systems in cattle exposed to polybrominated biphenyl.

In vivo and in vitro immunologic studies were undertaken in 114 Holstein cattle, 60 of which had detectable polybrominated biphenyls (PBB) in adipose tissue. The tissue PBB concentrations were between 0.02 and at least 1,000 mg/kg. An immunologic test profile was used to evaluate the influence of PBB on bovine immune competence. The profile included serum immunoglobulin determinations, autoantibody studies, lymphocyte subpopulation determinations, lymphoblastogenesis assays, delayed hypersensitivity skin testing, and neutrophil function studies. The results of the evaluation indicated that the host defenses are intact, both in quantity and function, in cattle with PBB body burdens ranging from 0.02 and 24.0 mg/kg for at least 2 years. Cattle fed 25 g of PBB daily during the acute toxicity study exhibited usual immune competence until they accumulated 500 g of PBB (tissue concentrations exceeding 1,000 mg/kg). Cattle that were fed more than 500 g of PBB became moribund and exhibited changes in neutrophil function tests and serum antibody titers.

Adipose Tissue↗
PubMed2001

Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity.

Defined tumor-associated antigens (TAA) are attractive targets for anti-tumor immunotherapy. Here, we describe a novel genome-wide approach to identify multiple TAA from any given tumor. A panel of transplantable thymomas was established from an inbred p53-/- mouse strain. The resulting tumors were examined for gene expression by mRNA microarray scanning. This analysis revealed heterogeneity of the tumors in agreement with the assumption that they represent different tumorigenic events. Several genes were overexpressed in one or more of the tumors. To examine whether overexpressed genes might be used to identify TAA, mice were immunized with mixtures of peptides representing putative cytotoxic T cell epitopes derived from one of the gene products. Indeed, such immunized mice were partially protected against subsequent tumor challenge. Despite being immunized with bona fide self antigens, no clinical signs of autoimmune reactions were observed. Thus, it appears possible to evaluate the entire metabolism of any given tumor and use this information rationally to identify multiple epitopes of value in the generation of tumor-specific immunotherapy. We expect that human tumors express similar tumor-specific metabolic imprints, which may be used to identify patient-specific arrays of TAA. This may enable a multi-epitope based immunotherapy with improved prospects of clinical tumor rejection.

Amino Acid Sequence↗
PubMed2001

A study of the pharmacokinetic profile of low-dose hepatitis B immune globulin in long-term liver transplant recipients for chronic hepatitis B infection.

Post-transplant protocols for hepatitis B (HBV) prophylaxis using high-dose intravenous hepatitis B immune globulin (10,000 IU) with or without lamivudine are commonly reported. Our centre has previously reported a low-dose intramuscular (i.m.) protocol and lamivudine with excellent results. There have been, however, no pharmacokinetic studies of i.m. hepatitis B immune globulin (HBIG) in this setting. The objective of this study was to determine the pharmacokinetic profile of i.m. HBIG in long-term post-liver-transplant recipients to determine a rational dosing protocol. Six stable liver transplant recipients receiving monthly i.m. HBIG injections for greater than one year were enrolled in this study. All patients had no detectable HBV DNA levels. HBIG titers (anti-HBs) were measured predose, then three times weekly for four weeks and then twice weekly until the serum HBIG titers were 100 IU/L or less. The pharmacokinetic parameters were calculated using noncompartment methods. The mean time to maximum concentration was 10.5 d (range 4-20 d) and the mean half-life was 20 d (range 13.5-23.5 d). Based on these pharmacokinetic parameters in stable long-term post-transplant patients, a rational dosing protocol was developed that allows for more appropriate utility of HBIG and improved patient convenience.

Area Under Curve↗
PubMed1978

The effect of passive immunization against estradiol on the regulatory profile and character of labor in the rat.

Treatment of pregnant rats with antiestradiol (A-E2) serum twice a day, starting at 2100 hours on day 19, sharply increased circulating total estradiol (E2) above control values and drastically reduced the biologically active E2 unbound (E2U) to A-E2 in plasma and uterine tissue. This A-E2-induced and--sustained E2U deficiency was not accompanied by similar changes in plasma and tissue progesterone (P), since P decreased similarly in the control and A-E2--treated rats in preparation for parturition. However, in the A-E2 rats the reduction in E2U was accompanied by a small, though significant, decrease in uterine vein prostaglandin F (PGF) during labor. This A-E2--provoked regulatory imbalance significantly altered normal parturition. In comparison with controls, labor in the A-E2 rats was delayed and prolonged by extended intervals between deliveries of individual fetuses of the same litter. The delay in the onset of labor significantly increased the birth weights of the newborn rats. Whether E2U deficiency is directly responsible for the asynchronic myometrial activity that delays and prolongs labor or whether it is mediated by reduced PGF release remains to be determined.

Animals↗
PubMed2006

Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues.

MicroRNAs are small approximately 22 nucleotide-long noncoding RNAs capable of controlling gene expression by inhibiting translation. Alignment of human microRNA stem-loop sequences (mir) against a recent draft sequence assembly of the bovine genome resulted in identification of 334 predicted bovine mir. We sequenced five tissue-specific cDNA libraries derived from the small RNA fractions of bovine embryo, thymus, small intestine, and lymph node to validate these predictions and identify new mir. This strategy combined with comparative sequence analysis identified 129 sequences that corresponded to mature microRNAs (miR). A total of 107 sequences aligned to known human mir, and 100 of these matched expressed miR. The other seven sequences represented novel miR expressed from the complementary strand of previously characterized human mir. The 22 sequences without matches displayed characteristic mir secondary structures when folded in silico, and 10 of these retained sequence conservation with other vertebrate species. Expression analysis based on sequence identity counts revealed that some miR were preferentially expressed in certain tissues, while bta-miR-26a and bta-miR-103 were prevalent in all tissues examined. These results support the premise that species differences in regulation of gene expression by miR occur primarily at the level of expression and processing.

Animals↗
PubMed2000

Autonomic performance and dehydroepiandrosterone sulfate levels in HIV-1-infected individuals: relationship to TH1 and TH2 cytokine profile.

BACKGROUND: Products of immune activation, including cytokines and lipid membrane derivatives, have been implicated in the pathogenesis of the neurologic sequelae, including autonomic dysfunction, associated with human immunodeficiency virus 1 (HIV-1) infection. In animal models, autonomic and endocrine dysfunction are associated with an altered cytokine profile. OBJECTIVES: To investigate the relationship between markers of immune activation (beta(2)-microglobulin), HIV-1 disease progression (CD4(+) cell count and viral load), and autonomic nervous system performance and to assess the relationship between autonomic performance, plasma levels of dehydroepiandrosterone sulfate (DHEAS), and T(H)1 and T(H)2 cytokine profile. METHODS: Thirty-one HIV-1-infected individuals and 22 HIV-1-negative controls were evaluated with a comprehensive neurologic, neuropsychological, and autonomic examination. Interleukin 4 and interferon gamma were measured by enzyme-linked immunosorbent assay in the supernatant of stimulated peripheral blood mononuclear cells. RESULTS: A composite measure of autonomic performance (AZ score) was significantly lower (worse autonomic function) in patients compared with controls (P=.04). A lower AZ score was associated with higher beta(2)-microglobulin serum levels and a lower CD4(+) cell count. Interleukin 4 levels were significantly inversely associated with AZ score (P=.01), whereas interferon gamma levels were significantly positively associated with DHEAS levels (P=.04). CONCLUSIONS: Our data show significant associations between markers of immune activation and disease progression and a composite measure of autonomic function in HIV-1-infected individuals. In addition, they suggest that poor autonomic function and low DHEAS plasma levels tend to be associated with an unbalanced cytokine profile.

Adult↗
PubMed2005

Retinoic acid amplifies the host immune response to LPS through increased T lymphocytes number and LPS binding protein expression.

Vitamin A deficiency is associated with increased susceptibility to infection but the effects of Vitamin A supplementation on host response to pathogens are controversial. This study investigated the mechanisms by which all-trans retinoic acid (atRA) modulates the host immune response in an experimental model of Vitamin A supplementation before and after challenge with LPS in rats. We show here that a supplementation with five daily injections of 10mg/kg atRA increased the number of T lymphocytes in the peripheral blood. In addition, we show that atRA increased the expression of the LPS binding protein (LBP), a component of the LPS recognition system. The retinoic acid receptor (RAR)alpha agonist Ro 4060-55 but not the pan-retinoid X receptors (RXRs) agonist Ro 2573-86 mimicked the effects of atRA on LBP expression suggesting that atRA enhances LBP expression through a RARalpha-mediated pathway. In order to investigate the significance of increased LBP expression we challenged atRA-supplemented rats with the Gram-positive bacteria Listeria monocytogenes (LM) that activates the immune response independently from LBP. In sharp contrast to our previous observations that atRA supplementation enhances IFN-gamma expression and NOS2 pathway activation in LPS-challenged rats [Devaux, Y., Grosjean, S., Seguin, C., David, C., Dousset, B., Zannad, F., Meistelman, C., de Talancé, N., Mertes, P.M., Ungureanu-Longrois, D., 2000. Retinoic acid and host-pathogen interactions: effects on inducible nitric oxide synthase in vivo. Am. J. Physiol. 279, E1045-E1053], atRA did not increase the LM-induced IFN-gamma expression and NOS2 pathway activation. Overall, these data demonstrate that although atRA induces a "priming" of the immune system characterized by increased T lymphocytes number and LBP expression, the profile of the immune response depends on the inflammatory/infectious stimulus. These results could explain why Vitamin A supplementation could have beneficial/neutral or deleterious effects according to the identity of the infectious pathogen.

Acute-Phase Proteins↗
PubMed2006

Pseudo-rationale design of efficient TB vaccines: lesson from the mycobacterial 27-kDa lipoprotein.

To develop or improve acellular vaccines against tuberculosis, scientists are in quest for the most efficient Th1 antigens. Immunization of mice with the M. tuberculosis 27-kDa antigen resulted in a strong Th1 immune response as indicated by serum analysis, splenocyte proliferation and cytokines secretion profile. Unexpectedly, mice immunized with 27-kDa turned out to be more susceptible to mycobacterial challenge as we found significant increase in the splenic cfu count compared to control groups. Moreover, the protection provided by BCG or other mycobacterial antigens was completely abolished once the 27-kDa antigen was added to the vaccine preparations. Further analysis of 27-kDa revealed that this lipoprotein is a B-cell mitogen, a feature that is known to be linked to enhanced virulence of the pathogen. However, by using the non-acylated form, 27DeltaSP, we excluded the involvement of the mitogenicity of 27-kDa in its deleterious effect. Currently, there is no explanation to the fact that the 27-kDa interferes with the protective immunity of other mycobacterial antigens; however, it is clear that 27-kDa need to be excluded from any future vaccine preparations. Indeed, we developed a multivalent vaccine that consists of six other mycobacterial antigens: 85B, 38-kDa, ESAT-6, CFP21, Mtb8.4 and 16-kDa. Immunization of mice with these antigens emulsified in Ribi adjuvant system and supplemented with recombinant IFN-gamma, resulted in strong Th1 immune response and a high protection level that was comparable to that of BCG.

Adjuvants, Immunologic↗