Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+rapamycin regimen.

BACKGROUND: Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect. METHODS: Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1). RESULTS: The proportion (%) of CD4+IL-2+ lymphocytes corresponding to CSA levels (mean+/-SD ng/ml) measured preoperatively (TO=O), and on postoperative day 8, before (356+/-63), and 2 hr after the morning dose (Cmax=1567+/-669), decreased from 39+/-16 to 15+/-8 and 3+/-1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4+IL-2-) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml (CSA concentration at which CD4+IL-2- cells increased by 50% over baseline) in an Emax pharmacodynamic model. CONCLUSIONS: Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, Cmax was associated with the least variable "cyclosporine effect." Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.

Long-term exercise patterns and immune function in healthy older women. A report of preliminary findings.

The purpose of this study was to examine the relationship between active versus inactive lifestyle and immunocompetence in older women. A sample of 46 independently dwelling, ambulatory and mentally alert women 60-98 years was examined, 25 who rated themselves as 'active' and 21 who rated themselves as 'inactive'. Lymphocyte subpopulations were analyzed by flow cytometry using selected monoclonal antibodies. The self-reported active subjects (also validated by their current unsolicited participation in a formal exercise class) demonstrated significantly higher percent change in CD25 mitogen stimulated lymphocytes (P = 0.0335) than those who reported themselves to be sedentary.

The influence of stress intrusion on immunodepression in generalized anxiety disorder patients and controls.

Previous work from our group has examined the relationship between stress and immunodepression in medical students taking National Boards, Part I, and has described a relationship between stress intrusion scores (SIS) and immunodepression. We have also shown that a high proportion of individuals with generalized anxiety disorders (GAD) and panic disorders (PD) exhibit enhanced stress intrusion (SI) and are more prone to upper respiratory infections (URI). In the present preliminary study, we sought to establish a model to evaluate further the role of SI level on the extent of immunodepression. This would serve to assess in further studies the mechanism(s) of stress-induced immunodepression, its relationship to morbidity, and the role of therapeutic interventions. In 14 GAD patients and 14 controls, we correlated the expression of interleukin-2 receptors (CD25) on T lymphocytes stimulated with anti-CD3 in short term cultures and the frequency of URI and the SIS to assess the relationships among these parameters. A decreased expression of CD25 correlates linearly with increasing SIS and with a higher number of sick days with URI. These results support our previous observations that GAD patients are more susceptible to URI. Moreover, they suggest that there may be a direct relationship between immunodepression and morbidity and between SIS and immunodepression.

Immunomodulatory effects of alpha interferon and thymostimulin in patients with neoplasias.

In this report, we have evaluated the immunological effects following administration of alpha interferon (IFN-alpha) in combination with thymostimulin (TP-1), as well as of IFN-alpha and TP-1 alone in patients with neoplasias who underwent surgery and were subsequently treated with conventional chemotherapy. Data suggest that the combination of IFN-alpha and TP-1 is the most effective in the up-regulation of some immune parameters such as the CD4(+)-CD8+ cell-dependent antibacterial activity. Since this immune function plays an important role in the host protection against different targets such as invading microorganisms and/or neoplastic cells, the administration of TP-1-IFN-alpha is advisable for patients with neoplasias under chemotherapy.

Alpha 1-acid glycoprotein (alpha 1-AGP) on the membrane of human lymphocytes: possible involvement in cellular activation.

A glycoprotein termed alpha 1-acid glycoprotein (alpha 1-AGP) is a component of normal human serum; its concentration is often increased in several pathological disorders, including acute inflammation and cancer. Inhibitory effects of alpha 1-AGP on some in vitro T and B cell function assays have been reported but our recent data indicated that alpha 1-AGP is indeed a T cell mitogen at physiological concentrations. The present study was designed to investigate: (a) the relationship between this glycoprotein and two other glycoproteins of the T and B cell membrane, i.e. the T3 and Ia antigens; (b) the ability of lymphocytes to take up exogenous alpha 1-AGP; (c) the different expression of alpha 1-AGP on the T cell membrane upon different activation pathways, i.e., autologous non-T-cells (B cells and monocytes) phytohemagglutinin and anti-T3 monoclonal antibody (MAb) stimulations. The data reported herein show no competition at the membrane level between anti-alpha 1-AGP and anti-T3 or anti-Ia MAbs. In addition, (1) the lymphocytes were able to absorb alpha 1-AGP from the culture medium and (2) the expression of this glycoprotein was enhanced upon T cell stimulation (all three stimulants employed induced an increase of alpha 1-AGP positive T cells), thus suggesting a possible role of this glycoprotein in in vitro T cell activation.

Does normal lymphocyte DNA synthesis in response to PHA exclude cell-mediated immunodepression?

PHA stimulation assay was the first in vitro method for evaluating the T-cell function, and this T-cell proliferative response has been routinely used to discriminate between normal subjects and patients with deficiency in cell-mediated immunity. However, [3H]thymidine incorporation into lymphocyte DNA can be studied by using additional in vitro assay methods since they measure different lymphocyte activation pathways. In the present study we selected three different tests to investigate the reliability of this single approach: PHA induced lymphocyte DNA synthesis; T lymphocyte DNA synthesis to anti-T3 monoclonal antibody (OKT3); autologous mixed lymphocyte reaction (AMLR). In addition, IL-2 receptor expression on the membrane of T-cell stimulated in AMLR both with PHA and anti-T3 was evaluated. This study was performed in various groups of subjects: normal young controls, aged healthy individuals, and patients with Alzheimer's disease (AD), Retinitis Pigmentosa (RP), and with cell-mediated immunodeficiency and clinical evidence of recurrent viral infections (ID). The data reported herein show heterogeneity of results in each group studied and demonstrate the necessity of employing more than one laboratory test for the routine evaluation of T-cell-mediated immunity.