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PubMed1986

Clinical and immunologic sequelae of AIDS retrovirus infection.

The Sydney AIDS Project is a prospective immunoepidemiological study of 911 homosexual and bisexual men enrolled between February 1984 and January 1985. Clinical, immunological, and serological studies are performed on these subjects every six months. At enrollment, 39.9% of subjects were seropositive for antibodies to AIDS retrovirus (ARV). Of these 352 seropositive subjects, 28.1% were symptomless with normal immune profiles, 23.6% were symptomless with an immunodeficiency, 18.8% had a clinical illness but normal immune profile, and 29.6% had a clinical illness and immunodeficiency. Of the symptomless subjects, 27.8% were seropositive for antibodies to ARV. Clinically, seropositivity was significantly associated with enlargement of three or more non-inguinal lymph node groups, splenomegaly, and hepatomegaly. Immunologically, seropositivity was significantly associated with lower absolute numbers of lymphocytes and T4+ lymphocytes and a lower T4+ : T8+ ratio, compared with seronegative subjects. Seropositive subjects with a clinical illness had a significantly lower percentage of T4+ lymphocytes and lower T4+ : T8+ ratio than did those who were symptomless. However, the absolute number of T4+ cells was not significantly different between subjects with a clinical illness and those who were symptomless. Subjects whose sera were positive by immunofluorescence and enzyme-linked immunosorbent assay but were negative by radioimmune precipitation assay had a lower number and percentage of T4+ lymphocytes than subjects who were positive by all three tests. These results demonstrate a wide variety of clinical and immunological responses to ARV infection. Prospective study of these subjects will enable us to define further the natural history of ARV infection and factors associated with progression.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Alterations in neutrophil (PMN) free intracellular alpha-keto acid profiles and immune functions induced by L-alanyl-L-glutamine, arginine or taurine.

The objective of this study was to determine the dose as well as duration of exposure-dependent effects of L-alanyl-L-glutamine, arginine or taurine on polymorphonuclear neutrophil (PMN) free alpha-keto acid profiles and, in a parallel study, on PMN immune functions. Exogenous L-alanyl-L-glutamine significantly increased PMN alpha-ketoglutarate, pyruvate PMN superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase (MPO) activity. Arginine also led to significant increases in alpha-ketoglutarate, pyruvate, MPO release and H2O2 generation. Formation of O2- on the other hand was decreased by arginine. Incubation with taurine resulted in lower intracellular pyruvate and alpha-ketobutyrate levels, decreased O2- and H2O2 formation and a concomitant significantly increased MPO activity. We therefore believe that considerable changes in PMN free-alpha-keto-acid profiles, induced for example by L-alanyl-L-glutamine, arginine or taurine, may be one of the determinants in cell nutrition that considerably modulates the immunological competence of PMN.

Adult↗
PubMed2002

Metallothioneins (I+II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply.

Thymic atrophy or thymus absence causes depressed thyroid-thymus axis (TTA) efficiency in old, young propyl-thiouracil (PTU) (experimental hypothyroidism) and in young-adult thymectomised (Tx) mice, respectively. Altered zinc turnover may be also involved in depressed TTA efficiency. Zinc turnover is under the control of zinc-bound metallothioneins (Zn-MTs) synthesis. Thyroid hormones, corticosterone and nutritional zinc affect Zn-MT induction. Zn-MT releases zinc in young-adult age during transient oxidative stress for prompt immune response. In constant oxidative stress (ageing and liver regeneration after partial hepatectomy), high liver Zn-MTs, low zinc ion bioavailability and depressed TTA efficiency appear. This last finding suggested that MT might not release zinc during constant oxidative stress leading to impaired TTA efficiency. The aim of this work/study is to clarify the role of Zn-MTs (I+II) in TTA efficiency during development and ageing. The main results are (1) Old and PTU mice display high corticosterone, enhanced liver MTmRNA, low zinc and depressed TTA efficiency restored by zinc supply. Increased survival and no significant increments in basal liver Zn-MTs proteins occur in old and PTU mice after zinc supply. (2) Lot of zinc ions bound with MT in the liver from old mice than young (HPLC). (3) Young-adult Tx mice, evaluated at 15 days from thymectomy, display high MTmRNA and nutritional-endocrine-immune damage restored by zinc supply or by thymus grafts from old zinc-treated mice. (4) Young-adult Tx mice, but evaluated at 40 days from thymectomy, display natural normalisation in MTmRNA and nutritional-endocrine-immune profile with survival similar to normal mice. (5) Stressed (constant dark for 10 days) mice overexpressing MT display low zinc, depressed immunity, reduced thymic cortex, high corticosterone, altered thyroid hormones turnover showing a likeness with old mice. These findings, taken altogether, show that corticosterone is pivotal in MTs induction under stress. MTs bind preferentially zinc ions in constant oxidative stress, but with no release of zinc from MT leading to impaired TTA efficiency. Zinc supply restores the defect because zinc has no interference in affecting pre-existing Zn-MTs protein concentrations in old and PTU mice. Therefore, free zinc ions are available for TTA efficiency after zinc supply. Thymus from old zinc-treated mice induces the same restoring effect when transplanted in Tx recipients. However, Tx mice display natural normalisation in MTmRNA and in nutritional-endocrine-immune profile in the long run. Therefore, Zn-MTs (I+II) are crucial in zinc homeostasis for endocrine-immune efficiency during the entire life assuming a role of potential and novel 'biological clock of ageing'.

Aging↗
PubMed2004

Effects of ornithine on neutrophil (PMN) free amino acid and alpha-keto acid profiles and immune functions in vitro.

The objective of this study was to determine the effects of ornithine on polymorphonuclear leucocyte (PMN) free amino- and alpha-keto acid profiles, superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase activity (MPO). Exogenous ornithine significantly increased PMN asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, alpha-ketoglutarate and pyruvate as intracellular ornithine increased. Concerning PMN immune function markers ornithine increased H2O2-generation and MPO activity while O2- -formation was decreased. We believe therefore that ornithine is important for affecting PMN "susceptible free amino- and alpha-keto acid pool" although the mechanisms are not yet clear. This may be one of the determinants in PMN nutrition considerably influencing and modulating PMN host defense capability.

Adult↗
PubMed2005

Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome.

BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in later February 2003, as a new epidemic form of life-threatening infection caused by a novel coronavirus. However, the immune-pathogenesis of SARS is poorly understood. To understand the host response to this pathogen, we investigated the gene expression profiles of peripheral blood mononuclear cells (PBMCs) derived from SARS patients, and compared with healthy controls. RESULTS: The number of differentially expressed genes was found to be 186 under stringent filtering criteria of microarray data analysis. Several genes were highly up-regulated in patients with SARS, such as, the genes coding for Lactoferrin, S100A9 and Lipocalin 2. The real-time PCR method verified the results of the gene array analysis and showed that those genes that were up-regulated as determined by microarray analysis were also found to be comparatively up-regulated by real-time PCR analysis. CONCLUSIONS: This differential gene expression profiling of PBMCs from patients with SARS strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response, rather than a specific immune response against a viral infection, as we observed a complete lack of cytokine genes usually triggered during a viral infection. Our study shows for the first time how the immune system responds to the SARS infection, and opens new possibilities for designing new diagnostics and treatments for this new life-threatening disease.

Antigens, Viral↗
PubMed2026

Peripheral immune markers and choroid plexus volumes as predictors of change in depressive symptoms: Insights from the EMBARC study.

Changes in choroid plexus (ChP) volume and peripheral inflammation have been associated with Major Depressive Disorder (MDD), yet their individual and combined impact on depressive symptoms is unclear. This study investigated whether baseline immune markers and ChP volumes predict changes in depressive symptoms during the 8-week treatment period among Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study participants who received either sertraline or placebo. Adults (n = 222) with MDD with peripheral blood samples were included. Circulating chemokines and cytokines were examined using a 40-plex assay. Depressive symptoms were assessed over 8 weeks using the Hamilton Depression Rating Scale (HAMD-17). Principal component analysis (PCA) was used for dimension reduction. Mixed-effects models were used to examine whether immune profiles and ChP volumes, and their interaction predicted HAMD-17, adjusting for demographic/clinical covariates and baseline depression severity. PCA identified three immune profiles. One profile, characterized by higher levels of cytokines and chemokines including IL-6, TNF-α, and IL-1β, was associated with greater depression severity, higher BMI, age, and CRP at baseline. Higher levels of these immune markers were associated with less improvement in depressive symptoms at 8 weeks (estimate = 1.211, p = 0.018) in models adjusting for right and left ChP volume (right ChP model: estimate = 1.034, p = 0.005; left ChP model: estimate = 0.993, p = 0.007). Interactions between immune markers and ChP volumes were not significant. Future investigations are warranted to examine the relationships between immune markers and ChP volume beyond structural changes in the context of depression symptoms.

Adult↗
PubMed2005

Comparisons of innate immune activity of all known living crocodylian species.

Serum samples from all twenty-three known living members of the Crocodylia were tested for antibacterial activity against eight bacterial species. These data were used to generate an immune profile for each crocodylian species. Statistical analyses revealed that the three living lineages of crocodylians, Alligatoroidea, Crocodyloidea, and Gavialoidea, were distinguishable by their immunological activities. For instance, species within the Alligatoroidea and Crocodyloidea exhibited remarkable immune activity similarities to others in their own lineages. Comparisons of the members of the different lineages, however, revealed substantial differences in immune profiles. Furthermore, species that are in the same genus were shown to exhibit more immune similarities to each other than to members of other genera within the same family. Finally, our immunological analyses reveal that Tomistoma schlegelii aligns more closely with the Gavialoidea than the Crocodyloidea.

Alligators and Crocodiles↗
PubMed2006

Epitomics: global profiling of immune response to disease using protein microarrays.

The immune system retains memory of current and past infections and can sense the presence of cancer by elaborating autoantibodies to tumor proteins. In the presence of an autoimmune disease, the immune system is an efficient, natural biosensor. Therefore we exploit the immune system through a high-throughput process to isolate disease-specific epitopes for diagnostic and therapeutic purposes. These cloned disease-specific antigens are robotically spotted onto protein microarrays and interrogated with serum from the subjects under analyses. These arrays deliver personalized profiles of antigenic exposures and therapeutic targets for personalized immunotherapy. The immune system is the ultimate biosensor, superior to anything a human could create and ready to be exploited for biotechnology and biomedicine.

Epitopes↗
PubMed2006

Co-administration of plasmid expressing IL-12 with 14-kDa Schistosoma mansoni fatty acid-binding protein cDNA alters immune response profiles and fails to enhance protection induced by Sm14 DNA vaccine alone.

Schistosomiasis is an endemic disease that affects 200 million people worldwide. DNA-based vaccine is a promising strategy to induce protective immunity against schistosomiasis, since both humoral and cellular immune responses are involved in parasite elimination. In this study, we evaluated the ability of Sm14 cDNA alone or in association with a plasmid expressing murine interleukin (IL)-12 to induce protection against challenge infection. Mice were immunized with four doses of the DNA vaccine and the levels of protection were determined by worm burden recovery after challenge infection. Specific antibody production to rSm14 was determined by ELISA, and cytokine production was measured in splenocyte culture supernatants stimulated with rSm14 and in bronchoalveolar lavage of vaccinated mice after challenge infection. DNA immunization with pCI/Sm14 alone induced 40.5% of worm reduction. However, the use of pCI/IL-12 as adjuvant to pCI/Sm14 immunization failed to enhance protection against challenge infection. Protection induced by pCI/Sm14 immunization correlates with specific IgG antibody production against Sm14, Th1 type of immune response with high levels of interferon (IFN)-gamma and low levels of IL-4 in splenocyte culture supernatants and in bronchoalveolar lavage after challenge infection. IL-12 co-administration with pCI/Sm14 induced a significant production of nitric oxide in splenocyte culture supernatants and also lymphocyte suppression, with reduced percentage of T cells producing IFN-gamma and tumor necrosis factor-alpha.

Animals↗
PubMed2001

Gene expression profiling in immune cells using microarray.

The recent development of DNA microarray, which offers the opportunity to study the expression of thousands of individual genes simultaneously in different biological systems, has provided new insights into the immune system. Examples discussed in this review include molecular descriptions of the differentiation program of T helper (Th) cells into Th1 and Th2 pathways and the genetic program underlying maturation of dendritic cells. It is anticipated that this new information can be used to understand gene function in both physiological and pathological conditions of the immune system.

Cell Differentiation↗
PubMed1996

Antibody reactivity profiles following immunization with diverse peptides of the PERB11 (MIC) family.

PERB11 (MIC) is a gene family possessing multiple copies located within the MHC. Structurally, PERB11 is related to the MHC class I, neonatal IgG Fc receptor (FcRn) and Zn-alpha 2-glycoprotein molecules. The MHC class I family is complex in terms of its genomic arrangement, expression and function, and available evidence suggests that the PERB11 family may be similarly complex. We have adopted an approach to study the expression of such complex gene families by immunizing with multiple peptides and by screening the resulting antibodies against a large range of tissues. The amino acid sequences of PERB11.1 and PERB11.2 as well as those of other related molecules were analysed and compared. Peptides were chosen for immunization based upon (i) loop formation within the equivalent known structure of the MHC class I molecules; (ii) immunogenicity by computer analysis; and (iii) evolutionary relationships. Antibodies in serum from immunized rabbits bound to three out of six peptides used for immunization. ELISA and immunoprecipitation demonstrated binding both to the peptides and to the PERB11.2 recombinant protein. By immunofluorescent staining of various tissues of several species, the three antisera generated overlapping profiles of activity. These included reactions with kidney, small and large intestine, oesophagus, testis, ovary and human neutrophils. This is the first description of antibodies induced by the PERB11 peptides. The extreme complexity of these profiles requires further investigation, but may be explained in terms of antibodies against diverse products of the PERB11 gene family and/or related molecules.

Amino Acid Sequence↗
PubMed2003

The leucocytic and parasitaemic profiles and immune response of rats treated with retinyl palmitate before infection with Trypanosoma brucei.

The effects of oral administration of retinyl palmitate (30,000 IU/kg bodyweight) for 3 days to rats before infection with Trypanosoma brucei were investigated by examining the leucocytic and parasitaemic profiles, and the antibody response to sheep red blood cells. The pretreatment significantly (P<0.01) improved the leucocytic profile (especially the absolute lymphocyte count) from day 7 post-infection to the time of death. It also significantly delayed the onset of parasitaemia (i.e., lengthened the pre-patent period) and led to reduced levels of parasitaemia throughout the period of infection. Pretreatment significantly increased the antibody response to sheep red blood cells (P<0.01) throughout the infection, even after treatment with diminazene aceturate, to levels that more than compensated for the immunosuppressive effect of the T. brucei. Further studies are warranted on the possible use of retinyl palmitate in overcoming immunosuppression associated with trypanosome infections in man and animals in endemic areas.

Animals↗
PubMed2000

Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile.

BACKGROUND: The C57BL/6J-Min/+ (Min/+) mouse bears a germline mutation in Apc and is therefore a model for familial adenomatous polyposis and sporadic colorectal cancer. Min/+ intestinal mucosa exhibits a marked tendency for spontaneous adenoma formation. Curcumin is a phenolic antioxidant known for its antitumor and immune modulatory functions in vitro. Curcumin prevents adenoma formation in Min/+ mice, through a mechanism that may be related to its immunomodulatory properties. MATERIALS AND METHODS: To study the relationship between intestinal immunity and curcumin-induced antitumor response, we used immunohistochemistry to characterize the effect of curcumin treatment on resident intestinal immune effector cells in Min/+ mice. RESULTS/CONCLUSION: These results show that mucosal CD4(+) T cells and B cells increase in animals treated with curcumin, suggesting that curcumin modulates lymphocyte-mediated immune functions.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Correlation between infection intensity, serum immunoglobulin profile, cellular immunity and the efficacy of treatment with praziquantel in murine schistosomiasis mansoni.

This study was conducted to evaluate the efficacy of praziquantel (CAS 55268-74-1, EMBAY 8440, Biltricide) in different grades of Schistosoma mansoni infection. Moreover, the relationship between the post treatment worm burden, hepatic granuloma volume, and serum immunoglobin profile was also investigated. Four groups of Swiss albino mice infected with Schistosoma mansoni cercariae were used: Highly infected untreated control mice (infected with 120 Schistosoma mansoni cercariae) and their corresponding praziquantel treated group. Lightly infected untreated control mice (infected with 60 Schistosoma mansoni cercariae) and their corresponding praziquantel treated group. Praziquantel was given seven weeks post infection in a dose of 500 mg/kg body weight for two consecutive days. Animals were sacrificed two weeks post treatment. Praziquantel achieved better cure rates in mice with heavy infection than in less intensely infected animals. The drug reduced the hepatic granuloma in animals with light intensity infection. This reduction was more accentuated in highly infected animals. The serum immunoglobulin profile (immunoglobulin G and immunoglobulin M) showed a higher level in highly infected treated mice (1.2 +/- 0.6 optical density unit and 1.1 +/- 0.5 optical density unit, respectively) and was reduced in animals with low intensity infection (1.18 +/- 0.6 optical density unit and 0.7 +/- 0.6 optical density unit, respectively). This study may be of value in tropical regions, where schistosomiasis with low worm burden is a common occurrence.

Animals↗
PubMed1995

Immune response profiles in vaccinated and non-vaccinated high- and low-responder mice during infection with the intestinal nematode Trichinella spiralis.

NIH and C57 BL/10 (B10) mice show genetically determined differences in their response to Trichinella spiralis infection. This study examines the influence of these on parameters of the immune response to infection after vaccination using muscle-larval excretory-secretory antigen in Freund's complete adjuvant. Serum antibody levels were greatly elevated when mice of both strains were vaccinated prior to infection; however, NIH produced significantly higher-level antibody responses than B10. Vaccination accelerated and increased the capacity of mesenteric lymph node T-cells to proliferate in vitro in response to specific antigen stimulation in both mouse strains but, in general, the stimulation indices of NIH cells were higher than those of the B10. The capacity of mesenteric lymph node cells (MLNC) and spleen cells (SC) to produce IL-5 and gamma IFN was measured after specific in vitro stimulation and early gamma IFN secretion was noted in the supernatants of NIH MLNC and SC, but not in B10 SC. Concentrations of IL-5 rose steadily over the first 10-14 days after infection in cell cultures from both strains. Prior vaccination of these animals appeared to enhance cytokine levels. It is postulated that the efficacy of vaccination in NIH mice is a consequence of their genetically determined capacity to produce early and high-level responses to the antigens of T. spiralis and to express these in intestinal effector mechanisms.

Animals↗
PubMed1979

Immune responsiveness in patients with choroidal malignant melanoma.

We studied selective in vivo and in vitro immunologic factors of 25 patients with choroidal malignant melanoma. Immune profile factors did not show consistent differences between patients with melanoma and an age-matched control population. The studies were also non-contributory in delineating variations in immunocompetence with respect to melanoma cell types. Serial immune profiles failed to identify a change when clinical evidence of metastasis developed. When tested as a group, patients with melanoma in whom metastatic disease developed during the study showed significant depression of initial mitogen-induced lymphocyte blastogenesis. This depression was noted in advance of clinically recognized metastatic disease. This group had a wide range of responses that overlapped those of control patients, thus making the usefulness of these testing factors questionable for individual prognosis or for clinical monitoring.

Adult↗
PubMed2004

A surrogate marker profile for PML/RAR alpha expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes.

BACKGROUND: The availability of genotype-specific therapy for PML/RAR alpha(pos) acute promyelocytic leukemia (APL) requires that this disease be precisely diagnosed. Immunophenotypic characteristics heretofore proclaimed as reliably characterizing APL (HLA-DR(low), CD34(low), P-glycoprotein(low) myeloid phenotype) do not differentiate from APL-like immune profiles unassociated with the PML/RAR alpha fusion transcript. METHODS: To establish a surrogate marker profile for APL, we explored 19 potentially predictive markers compared with differentiated acute myeloid leukemia using the classification tree approach with recursive partitioning. RESULTS: In a test group of 58 APL patients, the most predictive immune profile was HLA-DR(low), CD11a(low) (alpha(L) subunit of the leukocyte integrin LFA-1), CD18(low) (beta(2) subunit of LFA-1). APL cells always expressed CD117 (c-kit) but lacked the progenitor antigen CD133 and the more mature myeloid antigen, CD11b (alpha(M) leukocyte integrin). This antigen pattern was validated in 90 additional APL patients. M3v APLs (n = 30) had more leukemic promyelocytes expressing the T-cell antigen, CD2 (P < 0.0001) or the stem cell marker, CD34 (P = 0.0003) and demonstrated higher fluorescence intensity for the binding of antibody to the common leukocyte antigen, CD45 (P = 0.0008) than M3 (n = 102). S-form APL (n = 45) had a higher percent of cells expressing CD2 or CD34 (P < 0.0001 for both) or the neural cell adhesion molecule CD56 (P = 0.001) than L-form APL (n = 66). CONCLUSIONS: PML/RAR alpha(pos) APL cells typically lack leukocyte integrins. HLA-DR(low), CD11a(low), CD18(low) is a reliable surrogate antigen expression profile for PML/RAR alpha(pos) APL, irrespective of morphology and transcript isoform.

Antigens, Neoplasm↗
PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗