Increase In Lymphoproliferative Response Research Articles

Relationship between Regulatory T Cells and Immune Activation in Human Immunodeficiency Virus-Infected Patients Interrupting Antiretroviral Therapy

Persistent immune activation plays a central role in driving Human Immunodeficiency Virus (HIV) disease progression. Whether CD4+CD25+ regulatory T cells (Tregs) are harmful by suppressing HIV-specific immune responses and/or beneficial through a decrease in immune activation remains debatable. We analysed the relationship between proportion and number of regulatory T cells (Tregs) and immune activation in HIV-infected patients interrupting an effective antiretroviral therapy (ART). Twenty-five patients were included in a substudy of a prospective multicenter trial of treatment interruption (TI) (ANRS 116). Proportions and numbers of Tregs and the proportion of activated CD4 and CD8 T cells were assessed at baseline and month 12 (M12) of TI. Specific anti-HIV CD4 and CD8 responses were investigated at baseline and M12. Non parametric univariate analyses and multivariate linear regression models were conducted. At baseline, the proportion of Tregs negatively correlated with the proportion of HLA-DR+CD8+T cells (r = −0.519). Following TI, the proportion of Tregs increased from 6.3% to 7.2% (p = 0.029); absolute numbers of Tregs decreased. The increase in the proportion of HLA-DR+CD38+CD8+T cells was significantly related to the increase in proportion of Tregs (p = 0.031). At M12, the proportion of Tregs did not negatively correlate with CD8 T-cell activation. Nevertheless, Tregs retain a suppressive function since depletion of Treg-containing CD4+CD25+ cells led to an increase in lymphoproliferative responses in most patients studied. Our data suggest that Tregs are efficient in controlling residual immune activation in patients with ART-mediated viral suppression. However, the insufficient increase in the proportion and/or the decrease in the absolute number of Tregs result in a failure to control immune activation following TI.Trial RegistrationClinicalTrials.gov NCT00118677

Effects of Addition of Electrolyte and Ascorbic Acid in Feed during Heat Stress in Buffaloes

The ameliorative effect of salts and ascorbic acid polyphosphate supplementation on heat stress was studied in buffaloes. Adult buffaloes of either sex were randomly divided into 2 groups of 4 animals each. Group I served as control and Group II was supplemented with sodium bicarbonate, potassium carbonate and ascorbic acid polyphosphate. All the animals were exposed to two conditions of temperature and humidity: hot-dry and hot-humid in a psychrometric chamber for 4 h daily for 10 days. Blood was collected on day 1, 5 and 10 of treatment. The activities of catalase and superoxide dismutase (SOD), concentrations of serum glutathione (GSH), cortisol, sodium, potassium, and chloride and lipid peroxidation were estimated in serum. Lymphocyte proliferation was assessed in blood. The activities of catalase and SOD, serum concentration of GSH, sodium, potassium and chloride decreased while lipid peroxidation and serum cortisol increased in both groups when subjected to heat stress. Dietary supplementation resulted in further decreasing of the enzyme activities but increasing of the serum concentrations of GSH, sodium, potassium and chloride. Lipid peroxidation and serum cortisol increased in the supplemented group in both types of stress. Dietary supplementation caused an increase in lymphoproliferative response to con A. Thus, supplementation of ascorbate in addition to electrolytes relieves the animals of oxidative stress and boosts cell mediated immunity.

Dynamics of T Cells Subsets and Lymphoproliferative Responses During Structured Treatment Interruption Cycles and After Definitive Interruption of HAART in Early Chronic HIV Type-1-Infected Patients

Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.

A phase II trial of interleukin-12 in patients with advanced cervical cancer: clinical and immunologic correlates: Eastern Cooperative Oncology Group study E1E96

Purpose. The ability to mount lymphoproliferative responses to peptides derived from the human papillomavirus (HPV) E6 and E7 oncoproteins has been associated with regression of dysplastic lesions of the uterine cervix and loss of associated HPV infection. Interleukin-12 (IL-12) is a potent immunopotentiator of T-cell function, and has been shown in phase I clinical trials to be tolerable. Experimental design. Patients were required to have measurable metastatic, recurrent or inoperable cervical carcinoma. Patients could have had one prior adjuvant regimen and one prior regimen for advanced disease. Treatment consisted of IL-12 administered at 250 ng/kg IV as a rapid push in the outpatient setting daily × 5 every 21 days. Whole blood samples were acquired twice before treatment then approximately every 3 weeks to assess lymphoproliferative response in vitro to HPV type 16 (HPV 16) E4, E6, and E7 peptides. These responses were correlated with demographics and with clinical outcome. Results. Thirty-four patients were enrolled; 29 were evaluable. Over half had received cisplatin-based chemotherapy. The most common serious toxicities were hematologic or hepatic, and all were reversible. There was one partial responder (3%). The median survival was 6.5 months (95% CI: 5.8, 11.5 months). Eighteen of 29 eligible patients had evaluable laboratory data both pre- and post-therapy. There was a statistically significant increase in lymphoproliferative responses for HPV 16 E4, E6, and E7 peptides ( P = 0.020, 0.020, 0.043). There was a significant association between change in lymphoproliferative response to HPV 16 E6 peptides and number of cycles of treatment administered ( P = 0.048). There was no correlation between change in lymphoproliferative response to any peptide with age, performance status, race, prior chemotherapy, time from diagnosis to treatment, or with overall survival. Conclusions. IL-12 treatment was associated with improved lymphoproliferative responses to HPV 16 E4, E6, and E7 peptides. This is the first clinical trial to demonstrate induction of cell-mediated immune (CMI) responses to specific antigens (peptides) following treatment with IL-12 in women with cervical cancer. This improvement in immune response was not associated with enhanced objective response or survival.

Transient increase in mitogen-induced lymphoproliferative responses in patients with testicular cancer after BEP chemotherapy

Objectives. To investigate the impact of polychemotherapy on cellular immunity in patients with testicular cancer. Methods. Lymphocyte subpopulations, lymphoproliferative responses to mitogenic stimulation, and mitogen-induced release of soluble interleukin-2 receptor from peripheral blood mononuclear cells were investigated in 15 patients with testicular germ cell tumors a median of 61 months (range 7 to 73) after polychemotherapy with bleomycin, etoposide, and cisplatin (BEP). Results. The numbers of peripheral blood T cells (CD3+), CD4+ and CD8+ subsets, and lymphoproliferative responses to pokeweed mitogen, phytohemagglutinin, and concanavalin A in patients were comparable to those of healthy control subjects. When two groups of patients were formed according to elapsed time from BEP polychemotherapy and study onset (group A, 12 months and group B, 69 months after termination of BEP), a significant increase in lymphoproliferative response to concanavalin A ( P <0.05) was found in group A 1 year after chemotherapy. Conclusions. BEP chemotherapy administered to patients with testicular cancer does not result in impairment of cellular immunity but rather leads to a significant increase in the capacity of patients’ lymphocytes to respond to mitogenic stimulation up to 1 year after polychemotherapy. Moreover, the increased T-cell activity found after BEP therapy may contribute to the high rate of long-term complete remission.

Changes with aging and physical exercise in ascorbic acid content and proliferative response of murine lymphocytes

Ascorbic acid content and lymphoproliferative response to phytohemagglutinin were measured in lymphocytes from axillary nodes, spleen and thymus of young (15 ± 2 weeks) and old (60 ± 5 weeks) BALB/c mice. Ascorbic acid content in lymphocytes from spleen and thymus was found to be significantly higher and the lymphoproliferative response in the three immunocompetent organs significantly lower in old mice as compared to young mice. Moreover, young and old BALB/c mice were required to maintain a swimming activity until exhaustion (exhaustive exercise) or 90 min of swimming each day for a total of 20 days (continuous exercise). In both young and old mice the stress produced by exhaustive exercise and confirmed by the existence in serum of significantly increased levels of corticosterone compared to controls, caused a significant decrease in ascorbic acid content as well as in lymphoproliferative response. Continuous exercise, characterized by the presence in serum of significantly decreased levels of corticosterone compared to controls, produced the most significant decrease in ascorbic acid content from young and old murine lymphocytes. Moreover, this exercise resulted in a significant increase in lymphoproliferative response. Our results suggest that aging results in an increase in the ascorbic acid content of lymphocytes accompanied by a decline in the lymphoproliferative response in old BALB/c mice.

Lymphoproliferative Responses to Mitogen and Antigen in HIV-infected Children

We endeavored to study lymphoproliferative responses in children with human immunodeficiency virus (HIV) infection and to compare them with normal control children. Children were grouped according to age; 6-18 months and greater than 18 months, and according to CDC classification: asymptomatic (P1), mildly symptomatic (P2A), and advanced symptoms (P2D). Absolute CD4 and CD8 numbers were compared and found to be higher in the younger age groups. The children in P1 and P2A classes demonstrated an increase in CD8+ cells; only the children with AIDS showed a significant decrease in CD4+ cells. Lymphoproliferative responses to phytohemagglutinin A (PHA) were compared to tetanus toxoid. Only the children with acquired immunodeficiency syndrome (AIDS) (P2D) in the older group and only the symptomatic children (P2A and P2D) in the younger group showed a significant decrease in proliferative responses to PHA. All classes of infected children demonstrated a significant decrease in response to tetanus toxoid. We have been able to demonstrate a loss of antigen responsiveness which precedes the loss of mitogenic responsiveness. Furthermore, we have been able to demonstrate an age related increase in lymphoproliferative responses to both PHA and tetanus in HIV-infected and control children. Therefore, we conclude that children are particularly susceptible to the immunologic effects of HIV infection. Loss of lymphoproliferative responses to antigen occurs early in infected children and precedes the loss of CD4+ helper cells and of PHA responsiveness. This increased susceptibility to the immunopathogenesis of HIV infection is due, at least in part, to the relative immunodeficiency of infancy.