CD4 T-cell Numbers Research Articles

Generation of Neutralizing Antibodies and Divergence of SIVmac239 in Cynomolgus Macaques Following Short-Term Early Antiretroviral Therapy

Neutralizing antibodies (NAb) able to react to heterologous viruses are generated during natural HIV-1 infection in some individuals. Further knowledge is required in order to understand the factors contributing to induction of cross-reactive NAb responses. Here a well-established model of experimental pathogenic infection in cynomolgus macaques, which reproduces long-lasting HIV-1 infection, was used to study the NAb response as well as the viral evolution of the highly neutralization-resistant SIVmac239. Twelve animals were infected intravenously with SIVmac239. Antiretroviral therapy (ART) was initiated ten days post-inoculation and administered daily for four months. Viral load, CD4+ T-cell counts, total IgG levels, and breadth as well as strength of NAb in plasma were compared simultaneously over 14 months. In addition, envs from plasma samples were sequenced at three time points in all animals in order to assess viral evolution. We report here that seven of the 12 animals controlled viremia to below 104 copies/ml of plasma after discontinuation of ART and that this control was associated with a low level of evolutionary divergence. Macaques that controlled viral load developed broader NAb responses early on. Furthermore, escape mutations, such as V67M and R751G, were identified in virus sequenced from all animals with uncontrolled viremia. Bayesian estimation of ancestral population genetic diversity (PGD) showed an increase in this value in non-controlling or transient-controlling animals during the first 5.5 months of infection, in contrast to virus-controlling animals. Similarly, non- or transient controllers displayed more positively-selected amino-acid substitutions. An early increase in PGD, resulting in the generation of positively-selected amino-acid substitutions, greater divergence and relative high viral load after ART withdrawal, may have contributed to the generation of potent NAb in several animals after SIVmac239 infection. However, early broad NAb responses correlated with relatively preserved CD4+ T-cell numbers, low viral load and limited viral divergence.

Viability and Efficacy of Coverage of Cryopreserved Human Skin Allografts in Mice

Human skin allografts are considered one of the best temporary biological coverages for severe burn patients. Human skin allografts can be either viable or nonviable depending on their preservation modalities. However, there is a debate about the use of viable versus nonviable skin for severe burn patients because there is no established correlation between viability and efficacy of coverage. The authors tried to correlate the viability of cryopreserved human skin allografts as assessed by the MTT assay, with efficacy of coverage, intensity of rejection at day 8, and delay of wound healing in a xenograft model using human fresh skin (FS) and cryopreserved skin (CPS) on murine recipients (n = 49). Cryopreserved grafts were less rejectable than fresh grafts, with statistically significant different delays (P = .0008). Mice that had received grafts healed with delays; the delays, whether associated with fresh grafts or cryopreserved grafts, were not statistically significant. On day 8 after the graft, the overall damage score for the tissue's histological architectural integrity was higher for FS. Furthermore, flow cytometry analysis showed a significant increase in the number of CD4 and CD8 T-cells (P = .001) in the spleens of FS-grafted mice. These results confirm that the use of viable CPS does not change the potential for healing.

Modulating numbers and phenotype of CD8+ T cells in secondary immune responses

Prime-boost regimens are frequently used to increase the number of memory CD8(+) T cells and thus the protective capacity of experimental vaccinations; however, it is currently unknown how the frequency and phenotype of primary (1 degrees ) memory CD8(+) T cells impact the quantity and phenotype of secondary (2 degrees ) memory CD8(+) T-cell populations. Here, we show that 2 degrees infections of mice that received different 1 degrees infections and/or immunizations generated similar numbers of 2 degrees effector and memory CD8(+) T cells. Remarkably, this result was independent of the numbers and phenotype of 1 degrees memory CD8(+) T cells present at the time of rechallenge. However, after adoptive transfer of low numbers of 1 degrees memory CD8(+) T cells, a linear correlation between 1 degrees memory CD8(+) T-cell input and 2 degrees memory CD8(+) T-cell numbers was observed. These data suggest that, above a very low threshold, boosting of 1 degrees memory CD8(+) T-cell populations elicits 2 degrees immune responses of similar magnitude. Therefore, our study has important implications for the design of prime-boost regimens that aim to generate protective CD8(+) T-cell-mediated immunity.

Estimated average annual rate of change of CD4+T-cell counts in patients on combination antiretroviral therapy

Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4(+) T-cell count according to levels of viraemia in patients on cART. A total of 111,371 CD4(+) T-cell counts and viral load measurements in 8,227 patients were analysed. Annual change in CD4(+) T-cell numbers was estimated using mixed models. After adjustment, the estimated average annual change in CD4(+) T-cell count significantly increased when viral load was <500 copies/ml (30.4 cells/mm(3), 95% confidence interval [CI] 26.6-34.3), was stable when viral load was 500-9,999 copies/ml (3.1 cells/mm(3), 95% CI -5.3-11.5) and decreased when viral load was > or =10,000 copies/ml (-14.8 cells/mm(3), 95% CI -4.5--25.1). Patients taking a boosted protease inhibitor (PI) regimen had more positive annual CD4(+) T-cell count changes than patients taking other regimens for any given viral load strata: 30.9 cells/mm(3) (95% CI 27.7-34.1) when viral load was <500 copies/ml, 14.2 cells/mm(3) (95% CI -2.1-30.4) when viral load was 500-9,999 copies/ml and -19.9 cells/mm(3) (95% CI -36.6--3.3) when viral load was >or =10,000 copies/ml. By contrast, among patients taking a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, the CD4(+) T-cell count significantly decreased when the viral load was 500-9,999 copies/ml (-18.6 cells/mm(3), 95% CI -33.8--3.5) and decreased at a faster rate when the viral load was > or =10,000 copies/ml (-44.4 cells/mm(3), 95% CI -62.0--26.9; P=0.0012, test for interaction). On average, CD4(+) T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased in patients taking an NNRTI-based cART regimen when viral load was 500-9,999 copies/ml.

Interleukin-15 Receptor Blockade in Non-Human Primate Kidney Transplantation

Interleukin (IL)-15 is a chemotactic factor to T cells. It induces proliferation and promotes survival of activated T cells. IL-15 receptor blockade in mouse cardiac and islet allotransplant models has led to long-term engraftment and a regulatory T-cell environment. This study investigated the efficacy of IL-15 receptor blockade using Mut-IL-15/Fc in an outbred non-human primate model of renal allotransplantation. Male cynomolgus macaque donor-recipient pairs were selected based on ABO typing, major histocompatibility complex class I typing, and carboxy-fluorescein diacetate succinimidyl ester-based mixed lymphocyte responses. Once animals were assigned to one of six treatment groups, they underwent renal transplantation and bilateral native nephrectomy. Serum creatinine level was monitored twice weekly and as indicated, and protocol biopsies were performed. Rejection was defined as a increase in serum creatinine to 1.5 mg/dL or higher and was confirmed histologically. Complete blood counts and flow cytometric analyses were performed periodically posttransplant; pharmacokinetic parameters of Mut-IL-15/Fc were assessed. Compared with control animals, Mut-IL-15/Fc-treated animals did not demonstrate increased graft survival despite adequate serum levels of Mut-IL-15/Fc. Flow cytometric analysis of white blood cell subgroups demonstrated a decrease in CD8 T-cell and natural killer cell numbers, although this did not reach statistical significance. Interestingly, two animals receiving Mut-IL-15/Fc developed infectious complications, but no infection was seen in control animals. Renal pathology varied widely. Peritransplant IL-15 receptor blockade does not prolong allograft survival in non-human primate renal transplantation; however, it reduces the number of CD8 T cells and natural killer cells in the peripheral blood.

Translational medicine as implementation science in the field of monitoring HIV and TB. New concepts emanating from resource‐poor countries

In the last decade, there has been generous support by Western nations to deal with the HIV/AIDS epidemic and accompanying plethora of infections, a significant portion of the aid is extended to resource-restricted countries (1). The wave of support has contributed to the development of a branch of biomedical activity, referred to as translational medicine. This new field covers two areas: (i) the ‘‘translational medicine proper’’ (T-1) to establish proofs of concepts mostly in animal models that lead to pilot studies in humans, and (ii) ‘‘the translational medicine-2’’ (T-2, also referred to as ‘‘implementation science’’) for optimizing already established medical concepts in rich and poor countries alike, for wider applications in communities (2). Fledgling journals which carry the ‘‘translational’’ title clearly favor T-1 publications; by contrast, on the pages of Clinical Cytometry mostly T-2 topics are featured as clinical implementations of diagnostically relevant developments. For two reasons, the T-2 field is subject to political scrutiny. First, In 2008, US $ 15.6 billion was spent on AIDS programs in low and middle income countries. Currently, a very high proportion (50%) of these are coming from external, including generous North American, sources and these may not be sustainable. Furthermore, the calculated trends reveal that this expenditure is to shoot up to 2–3 times higher levels, and that a major epidemic will still be with us in 2031 without a change in approach (3). Second, medical care in the West is, by tradition, expensive (4). The health care practiced in the US appears to be in the 37th position with respect to cost efficiency (5). Consequently, when suggesting that from now on the resource-restricted partners must contribute more to their HIV care/prevention (3), the possibilities of modifying diagnostics according to the local needs using local implementation science must be considered. This field in Africa has been revitalized since generic antiretroviral therapy (ART) became affordable. During the last decade requirements for simplifying diagnostics has frequently been advocated in the pages on Clinical Cytometry (6,7). When African health care workers are faced with acute crisis, they are often proven to be inventive. Evidence is gathering that the technologists in resource-poor regions are capable of developing and/or modifying methods in order that these are elegantly simplified for more affordable large scale testing formats. Some of these efforts represent improvements of precision, accuracy, quality assessment, and training (8–10). In his recent book, Nigel Crisp, the former Chief Executive of the National Health Service of the United Kingdom (11) explains that ‘‘poor countries do not need a diluted version of what rich countries have now, and may have an easier time building a better system from little.’’ Inspired by his approach, in this editorial, we would like to briefly review five recent papers (12–16). But first we need to consider two significant changes in the global outlook which influence the use of diagnostics. In 2006, the WHO recommended that all HIV positive patients start ART when their CD4 T-cell count fell to 200 cells/mm. In patients with CD4 counts between 200 and 350 cells/mm, the initiation of ART was optional on the basis of these patients showing some symptoms (Grade 2–4) or were still asymptomatic (Grade 1). However, in countries with poor resources this guideline was frequently interpreted as to start ART at 200/mm, reaching many patients too late (17,18) even at levels as low as 50–150 CD4 T-cells/mm. Recently, it has also been shown that earlier start of ART at higher CD4 T-cell counts reduces mortality and morbidity rates (17,18). Therefore WHO, in unison with other regulatory bodies, now recommends ART to be

Thymic involution and proliferative T-cell responses in multiple sclerosis

We investigated naïve CD4 T-cell homeostasis in relapsing–remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.

Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328)

BackgroundEffective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.ResultsThe patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm3 at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed.ConclusionsAlthough sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease.Trial RegistrationA5051 ClinicalTrials.gov Identifier: NCT00000923.

Sustained low‐dose growth hormone therapy optimizes bioactive insulin‐like growth factor‐I level and may enhance CD4 T‐cell number in HIV infection

High-dose recombinant human growth hormone (rhGH) (2-6 mg/day) regimes may facilitate T-cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high-dose rhGH regimens increase insulin-like growth factor-I (IGF-I) to supra-physiological levels associated with severe side effects. The present study investigated whether lower doses of rhGH may improve T-cell restoration in patients infected with HIV following an expedient response of total and bioactive (i.e., free) IGF-I. A previous 16-week pilot-study included six HIV-infected patients on stable HAART to receive rhGH 0.7 mg/day, which increased total (+117%, P < 0.01) and free (+155%, P < 0.01) IGF-I levels. The study was extended to examine whether continuous use of low-dose rhGH (0.7 mg/day until week 60; 0.4 mg/day from week 60 to week 140) would maintain expedient IGF-I levels and improve CD4 T-cell response. Total and free IGF-I increased at week 36 (+97%, P < 0.01 and +125%, P < 0.01, respectively) and week 60 (+77%, P = 0.01 and +125%, P < 0.01) compared to baseline levels (161 +/- 15 and 0.75 +/- 0.11 microg/L). CD4 T-cell number increased at week 36 (+15%, P < 0.05) and week 60 (+31%, P = 0.01) compared to baseline levels (456 +/- 55 cells/microL). Following rhGH dose reduction, total IGF-I and CD4 T-cell number remained increased at week 88 (+44%, P = 0.01 and +33%, P < 0.01) and week 140 (+46%, P = 0.07 and +36%, P = 0.02) compared to baseline levels. These data support the notion that low-dose rhGH regimens may increase expediently total and bioactive IGF-I and improve T-cell restoration in patients infected with HIV on HAART.

Loss of HIV-specific memory B-cells as a potential mechanism for the dysfunction of the humoral immune response against HIV

A central, yet unresolved issue in the pathogenesis of HIV disease is the mechanism of antibody perturbation. In this study, HIV-specific memory B-cells were quantified in groups of infected subjects and compared with memory responses to other antigens and antibody titers. HIV-specific memory B-cell responses were vigorous in individuals with CD4(+) T-cell counts >350/microl and weak or undetectable in subjects with CD4(+) T-cell numbers <200/microl. Memory B-cell loss was permanent, because antiretroviral therapy failed to restore HIV-specific memory responses while influenza- and tetanus toxoid-specific memory B-cells remained unaffected or recovered. Antibody titers to Gag strongly correlated with memory B-cell frequencies. In contrast, Env-specific antibodies were maintained in advanced disease despite low or undetectable levels of memory B-cells. These results provide a potential mechanism by which destruction of HIV-specific CD4(+) T-cells affects the humoral immune response against HIV and compromises the ability to maintain an effective antibody response.

Plasmodium falciparum Infection Significantly Impairs Placental Cytokine Profile in HIV Infected Cameroonian Women

BackgroundPlacental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women.Materials and Methods P. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses.ResultsPlacental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5–4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3–1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-α mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-α/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-α was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery.ConclusionsThese results show that P. falciparum infection profoundly modifies the placenta cytokine environment and acts as a confounding factor, masking the impact of HIV-1 in co-infected women. This interplay between the two infections might have implications in the in utero MTCT of HIV-1 in areas where HIV-1 and P. falciparum co-circulate.

Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma

We investigated whether tumor-specific CD8(+) T-cell responses affect tumor-free survival as well as the relationship between CD8(+) T-cell responses against tumor-associated antigens (TAAs) and the clinical course after tumor treatment in patients with hepatocellular carcinoma (HCC). Twenty patients with HCC that were treated by radiofrequency ablation or trans-catheter chemo-embolization (TACE) and in whom HCC was undetectable by ultrasonography, CT, and/or MRI 1 month after treatment were enrolled in the study. Before and after treatment for HCC, analyses of TAA (glypican-3, NY-ESO-1, and MAGE-1)-specific CD8(+) T-cell responses were evaluated with an interferon-gamma enzyme-linked immunospot (ELISpot) assay using peripheral CD8(+) T-cells, monocytes, and 104 types of 20-mer synthetic peptide overlapping by 10 residues and spanning the entirety of the 3 TAAs. Sixteen out of 20 patients (80%) showed a positive response (> or = 10 TAA-specific cells/10(5) CD8(+) T-cells) before or after treatment. When we performed univariate analysis of prognostic factors for the tumor-free period in the 20 patients, platelet count, prothrombin time, and the number of TAA-specific CD8(+) T-cells after treatment were significant factors (P = 0.027, 0.030, and 0.004, respectively). In multivariate analysis, the magnitude of the TAA-specific CD8(+) T-cell response (> or = 40 TAA-specific cells/10(5) CD8(+) T-cells) was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, P = 0.022). Our results suggest that strong TAA-specific CD8(+) T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy.

Inhibition of Phosphoinositide 3-Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.

Vaccination with SIVmac239Δnef activates CD4+ T cells in the absence of CD4+ T‐cell loss

Pathogenic HIV and SIV infections characteristically deplete central memory CD4(+) T cells and induce chronic immune activation, but it is controversial whether this also occurs after vaccination with attenuated SIVs and whether depletion or activation of CD4(+) T-cell play roles in protection against wild-type virus challenge. Rhesus macaques were vaccinated with SIVmac239Deltanef and quantitative and phenotypic polychromatic flow cytometry analyses were performed on mononuclear cells from blood, lymph nodes and rectal biopsies. Animals vaccinated with SIVmac239Deltanef demonstrated no loss of CD4(+) T cells in any tissue, and in fact CCR5(+) and CD28(+)CD95(+) central memory CD4(+) T cells were significantly increased. In contrast, CD4(+) T-cell numbers and CCR5 expression significantly declined in unvaccinated controls challenged with SIVmac239. Also, intracellular Ki67 increased acutely as much as 3-fold over baseline in all tissues after SIVmac239Deltanef vaccination then declined following primary infection. We demonstrated in this study that SIVmac239Deltanef vaccination did not deplete CD4(+) T cells but transiently activated and expanded the memory cell population. However, increases in numbers and activation of memory CD4(+) T cells did not appear to influence protective immunity.

Interleukin‐12 is sufficient to promote antigen‐independent interferon‐γ production by CD8 T cells in old mice

Numerous functional defects have been identified in naive T cells from aged mice, including deficiencies in proliferation, cytokine production and signal transduction. It is well documented that the ratio of naïve to memory T cells significantly decreases with age resulting in the majority of T cells from aged hosts expressing activated/memory T-cell markers (CD44(hi)), yet it is unclear whether T cells with a CD44(hi) phenotype in aged hosts are functionally equivalent to T cells with a similar phenotype in young hosts. We have identified a population of CD44(hi) CD8 T cells in old mice that are capable of secreting interferon-gamma (IFN-gamma) in response to interleukin-12 (IL-12) stimulation. This occurred in the absence of T-cell receptor engagement, a function that was not observed in CD8 T cells from young mice. This phenotype was associated with increased IL-12 receptor beta2 gene expression and IL-12 induced signal transducer and activator of transcription 4 (STAT-4) activation, even when CD8 T-cell numbers from young and old mice were normalized for CD44(hi) expression. Furthermore, we demonstrate that IL-12-induced STAT-4 activation was required for T helper type 1 (Th1) cytokine-induced IFN-gamma production in CD8 T cells. These data illustrate that old mice possess a specialized subset of CD44(hi) CD8 T cells with an enhanced responsiveness to IL-12, enabling these cells to produce substantial amounts of IFN-gamma in response to Th1 cytokine stimulation. We have therefore identified a functional difference in the populations of CD44(hi) CD8 T cells from young and old mice, and believe that understanding age-associated immunological changes is essential for helping the elderly combat deadly diseases.

Attenuation of the Systemic Inflammatory Response and Infectious Complications After Gastrectomy with Preoperative Oral Arginine and ω‐3 Fatty Acids Supplemented Immunonutrition

Past trials have shown perioperative immunonutrition to improve the outcome for patients with gastric cancer. The present study was designed to evaluate the effect of preoperative oral immunonutrition on cellular immunity, the duration of the systemic inflammatory response syndrome (SIRS), and detailed postoperative complications in patients with gastric cancer. Sixty patients with gastric cancer were randomly assigned to two groups: one group received immune-enhanced formulas supplemented with arginine and omega-3 fatty acids (immune-enhancing diet (ID) group, n = 30); the other received standard formulas (conventional diet (CD) group, n = 30) for 7 days before the operation. These groups were well matched in terms of age, sex, operations, cancer stages, and intraoperative variables. The postoperative outcome was evaluated based on clinical variables, including postoperative infectious complications, noninfectious complications, and SIRS duration. In addition, the perioperative state of cellular immunity was evaluated and compared between the two groups. The incidence of postoperative infectious complications in the ID group (6%) was significantly (p < 0.05) lower than that of the CD group (28%). The duration of SIRS in the ID group (0.77 +/- 0.9 days) was significantly (p < 0.05) shorter than that in the CD group (1.34 +/- 1.45 days). The postoperative lymphocyte and CD4(+)T-cell counts significantly decreased (p < 0.05) in both groups. However, the number of CD4(+)T-cells on preoperative day 1 and postoperative day 7 was significantly (p < 0.05) higher in the ID group than in the CD group. Preoperative oral immune-enhanced formulas supplemented with arginine and omega-3 fatty acids enhanced the immune status of the patients, reduced the duration of SIRS, and decreased the incidence of postoperative infectious complications. CD4(+)T-cell immunity likely played an important role in the modulation of the postoperative immune and inflammatory response after gastrectomy.

Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers

BackgroundHIV-1+ individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4+ T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.Methodology/Principal FindingsCD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-γ ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1+ individuals originally identified as “Long-term non-progressors” in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-γ producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-γ production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1+ patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-γ production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.ConclusionsAlthough increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory.

Magnitude of CD8+ T‐cell responses against hepatitis C virus and severity of hepatitis do not necessarily determine outcomes in acute hepatitis C virus infection

We investigated the relationship between the magnitude of comprehensive hepatitis C virus (HCV)-specific CD8(+) T-cell responses and the clinical course of acute HCV infection. Six consecutive patients with acute HCV infection were studied. Analysis of HCV-specific CD8(+) T-cell responses was performed using an interferon-gamma-based enzyme-linked immunospot assay using peripheral CD8(+) T-cells, monocytes and 297 20-mer synthetic peptides overlapping by 10 residues and spanning the entire HCV sequence of genotype 1b. Five patients presented detectable HCV-specific CD8(+) T-cell responses against a single and different peptide, whereas 1 patient showed responses against three different peptides. Neither the magnitude of HCV-specific CD8(+) T-cell responses nor the severity of hepatitis predicts the outcome of acute hepatitis. The maximum number of HCV-specific CD8(+) T-cells correlated with maximum serum alanine aminotransferase level during the course (r = 0.841, P = 0.036). HCV-specific CD8(+) T-cell responses were detectable in all 6 patients with acute HCV infection, and 6 novel HCV-specific CTL epitopes were identified. Acute HCV infection can resolve with detectable HCV-specific CD8(+) T-cell responses, but without development of antibody against HCV.

Antigen-specific T-T interactions regulate CD4 T-cell expansion

AbstractThe regulation of CD4 T-cell numbers during an immune response should take account of the amount of antigen (Ag), the initial frequency of Ag-specific T cells, the mix of naive versus experienced cells, and (ideally) the diversity of the repertoire. Here we describe a novel mechanism of T-cell regulation that potentially deals with all of these parameters. We found that CD4 T cells establish a negative feedback loop by capturing their cognate major histocompatibility class (MHC)/peptide complexes from Ag-presenting cells and presenting them to Ag-experienced CD4 T cells, thereby inhibiting their recruitment into the response while allowing recruitment of naive T cells. The inhibition is Ag specific, begins at day 2 (long before Ag disappearance), and cannot be overcome by providing new Ag-loaded dendritic cells. In this way, CD4 T-cell proliferation is regulated in a functional relationship to the amount of Ag, while allowing naive T cells to generate repertoire variety.

Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study.

Immunotherapy is being increasingly utilized for adjuvant treatment for breast cancer (BC). We have previously described immune functions during primary therapy for BC. The present study describes immune recovery patterns during long-term, unmaintained follow-up after completion of adjuvant therapy.A group of patients with primary BC had been treated with adjuvant radio-chemotherapy (RT + CT) 5-fluorouracil, epirubicin and cyclophosphamide (FEC) (n = 21) and another group with radiotherapy (RT) (n = 20) alone. Immunological testing of NK and T-cell functions was performed initially at the end of adjuvant treatment and repeated after 2, 6 and 12 months. NK cell cytotoxicity was significantly higher (P < 0.05) at all time-points in patients than in age-matched controls and did not differ between the two treatments groups during one year observation. In contrast, lower numbers of CD4 T-cells and lower expression of CD28 on T-cells was observed particularly in RT + CT patients and did not normalize during the observation period. The numbers of T(reg) cells (CD4(+)CD25(high)) were low in the RT + CT group during follow-up, as well as expression of TCRxi, Zap70, p56(lck), P59(fyn) and PI3 k in CD4(+) cells. In contrast, expression of intracellular cytokines (IFN-gamma, IL-2, IL-4) in CD4 and CD8 T cells were significantly higher in RT + CT patients than in the RT group and the difference increased during follow-up. In conclusion, NK-cell cytotoxicity increased during unmaintained long-term follow-up whereas CD4 and regulatory T cells as well as signal transduction molecules remained low following adjuvant radio-chemotherapy.