CD4+ lymphocyte function with early human immunodeficiency virus infection.

The pathogenesis of cellular immune deficiency following human immunodeficiency virus (HIV) infection could result from quantitative and/or qualitative dysfunction of the CD4+ lymphocyte population. To better characterize the T-cell response to soluble antigen with HIV infection, we have isolated peripheral blood lymphocytes and purified populations of CD4+ lymphocytes from healthy HIV antibody-positive subjects, patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC), and healthy HIV antibody-negative controls. T-lymphocyte function was determined by proliferative response to lectin (phytohemagglutinin), phorbol 12-myristate 13-acetate (PMA), calcium ionophore, purified recombinant HIV envelope gp120, tetanus toxoid antigen, and tetanus toxoid antigen in the presence of recombinant gp120 or purified recombinant soluble CD4. PBLs and CD4+ lymphocytes from asymptomatic HIV-infected subjects responded equally well to lectin, PMA, and/or calcium ionophore and to tetanus toxoid as cells from uninfected control subjects. The cells that proliferated in response to a soluble antigenic stimulus did not respond to gp120. Cells from subjects with ARC had a selective antigen recognition defect independent of the number of CD4+ lymphocytes. Recombinant gp120 inhibited CD4+ lymphocyte proliferation to antigenic stimulus by 30-40%. Recombinant soluble CD4, a proposed therapeutic for HIV, had no effect on T-cell response to antigen. A selective antigen recognition response was not compromised early in HIV infection but was compromised in subjects with ARC. Inhibition of proliferation to tetanus toxoid by gp120 suggests that HIV may affect major histocompatibility complex II restricted antigen recognition independent of CD4+ cell loss.     

In vitro immunoglobulin production, proliferation, and cell markers before and after antithymocyte globulin therapy in patients with aplastic anemia

Peripheral blood lymphocytes from 16 aplastic anemia patients were studied for in vitro biosynthesis of immunoglobulins (Ig), proliferative responses, and cell markers before and after antithymocyte globulin (ATG) treatment in an attempt to identify immune functions that would be useful in predicting responses to ATG therapy. Six of the 16 aplastic anemia patients were complete responders to ATG therapy, two were partial responders, and eight failed to respond to ATG therapy. The proportion of E+, CD4, CD8, and surface Ig-positive cells did not correlate with in vitro lymphocyte functions nor clinical responses before or after ATG therapy. Lymphocyte proliferative responses to phytohemagglutinin, tetanus toxoid, alloantigens, or pokeweed mitogen were generally present before and after ATG therapy. When pokeweed mitogen, herpes simplex type I virus, and tetanus toxoid were used as probes to elicit in vitro Ig production using a hemolytic plaque assay, some patients had 1) B cells that failed to produce Ig, 2) T cells that failed to provide helper activity, and 3) T cells that exhibited excessive suppressor activity in the various antibody production systems. These measures of immune function, however, did not correlate with clinical responses to ATG therapy.     

Activation of lymphocytes induced by recombinant human granulocyte-macrophage colony-stimulating factor in patients with malignant lymphoma

To investigate effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on lymphoid cells in vivo, we monitored changes in absolute lymphocyte counts, plasma concentrations of soluble interleukin-2 receptor (sIL-2R) and soluble cytotoxic/suppressor (sCD8) antigens, and phenotypic changes of surface membrane antigens of peripheral mononuclear cells from 14 patients with malignant lymphoma treated with rhGM-CSF. Eight of the 14 patients had relapsed or had refractory non-Hodgkin's lymphoma (NHL) and received rhGM-CSF after intensive chemotherapy with novantrone (NO) and high-dose Ara-C (AC) (NOAC) as salvage regimen. Six other patients with NHL or Hodgkin's disease (HD) were in complete remission and treated with rhGM-CSF to enhance peripheral hematopoietic progenitor cell harvest for autografting. An increase in absolute lymphocyte count at the zenith of leukocyte elevation and a drastic increase in concentration of sIL-2R from a median of 565 U/mL to 6,700 U/mL on rhGM-CSF infusion were found in all patients. There was also a moderate increase in sCD8 levels from a median of 277 U/mL to 470 U/mL. Ten patients were available for serial studies of phenotypic changes in surface membrane antigens. A significant increase in CD25+ (IL-2R+) (P = .0020) and CD4+ (P = .0137) lymphocytes was observed in all patients, but no significant change in CD3+, CD8+, TCR delta 1+, or CD19+ cells. Elevations in absolute lymphocyte counts or in concentrations of sIL-2R or sCD8 were not observed in four other patients during recovery from intensive chemotherapy without rhGM-CSF support. Our results provide evidence that administration of rhGM-CSF might activate lymphocytes in vivo. The impact of this activation on the remission rate and duration, as well as survival in patients with NHL, warrants further investigation.     

Varicella zoster virus--specific immune response after treatment with sodium stibogluconate for cutaneous leishmaniasis

Sodium stibogluconate has been associated with the reactivation of varicella zoster virus (VZV) in otherwise healthy adults who receive the drug as treatment for cutaneous leishmaniasis. Ten patients receiving daily sodium stibogluconate underwent phlebotomy at baseline and at day 10. Flow cytometry-based immunophenotyping, VZV-specific IgG levels, and lymphocyte proliferative responses and intracellular cytokine secretion to VZV, cytomegalovirus, tetanus toxoid, superantigen, and mitogens were performed at both time points. The absolute number of total leukocytes, total lymphocytes, and lymphocyte subsets decreased overall without predilection for any particular subset of lymphocytes, such that the percentage of the total lymphocyte population for each lymphocyte subset did not change significantly (except for a marginal increase in percentage of cytotoxic T cells). Antibodies to VZV were measured in seven patients before and after treatment, and did not change. Lymphocyte proliferative responses to VZV and other antigens and mitogens did not change from baseline. The mechanism for the increased rate of VZV reactivation after treatment with sodium stibogluconate remains undefined.     

Suppressive effect of granulocyte-macrophage colony-stimulating factor on the generation of natural killer cells in vitro.

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant human granulocyte-CSF (rhG-CSF) on the generation of natural killer (NK) cells in vitro. NK cells were cultured from selected human bone marrow cells obtained after the elimination of mature T and NK cells. rhGM-CSF significantly suppressed the generation of CD56+ cells and NK activity (P less than .01) in a dose-dependent manner. The generation of large granular lymphocytes (LGL) was also suppressed in the presence of rhGM-CSF (P less than .01). In contrast, rhG-CSF had no effect on LGL (P greater than .05). Both rhGM-CSF and rhG-CSF had no influence on the CD56+ cell count in the peripheral blood. These results suggest that rhGM-CSF suppresses the in vitro generation of NK cells.     

A combined stress hormone infusion decreases in vivo protein synthesis in human T lymphocytes in healthy volunteers.

In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infusion given to healthy volunteers as a human trauma model. Here, the purpose was to further investigate this finding and to measure in vivo protein synthesis in isolated T lymphocytes. Furthermore, the effects of stress hormones on the lymphocyte subpopulations and mononuclear cells, characterized by flow cytometry and phytohemagglutinin (PHA)-induced and unstimulated proliferative responses in vitro, were elucidated. Healthy volunteers (n = 16) were randomized into 2 groups to receive either a stress hormone or a saline infusion for 6 hours. In vivo protein synthesis was studied before and after the treatment by measuring the incorporation of stable isotopically-labeled phenylalanine into lymphocyte and mononuclear cell proteins. Protein synthesis decreased after stress hormone infusion in both cell populations: in T lymphocytes from 13.0% +/- 0.7%/d (mean +/- SD) to 8.6% +/- 2.1%/d (P <.01) and in mononuclear cells from 13.3% +/- 1.2%/d to 6.3 +/- 2.0%/d (P <.001). No change in proliferative responsiveness in vitro was observed. The stress hormone infusion produced a decrease in the percentage of T helper CD3/CD4 from 41% to 18% (P <.001), T cytotoxic CD3/CD8 from 27% to 15% (P <.001), as well as total T CD3 cells from 69% to 35% (P <.001). There was an increase in the percentage of natural killer (NK) cells CD16/CD56 from 17% to 55% (P <.001). Determination of phenotypes expressed on activated T lymphocytes showed that CD3/HLA-DR was unchanged and CD3/CD25 decreased from 14% to 7% (P <.01) in the stress hormone group. The study showed that the decrease of in vivo protein synthesis was 34% in T lymphocytes as compared with 53% in mononuclear cells, when determined immediately after a 6-hour stress hormone infusion. This change was associated with a pronounced decrease in all lymphocyte subpopulations, except for the NK cells, which increased substantially.     

Human Lymphocyte Populations in Blood after Tetanus Vaccination

The content of circulating T and B lymphocytes in 9 healthy volunteers was estimated before and after secondary vaccination with tetanus toxoid. E, Fc, and C3 receptors were demonstrated by rosette techniques and surface Ig by fluorescence technique. The absolute number of T and non-T (B) lymphocytes was simultaneously increased during the first 48 h and at 144 h after vaccination. The correlation between paired T and non-T (B) lymphocyte counts was enhanced after vaccination, prolbably reflecting mechanisms governing the traffic of lymphocytes.     

Limited proliferative response to type II collagen in rheumatoid arthritis

In order to define the potential importance of type II collagen in the activation of rheumatoid arthritis (RA) synovial fluid (SF) lymphocytes, we examined the proliferative response of matched peripheral blood and SF lymphocytes to type II collagen. The mean proliferative response to the collagen was somewhat greater (p less than 0.05) with SF, compared to peripheral blood lymphocytes. However, the magnitude of this response was relatively weak as determined by stimulation indices, and it did not approach that observed with peripheral blood lymphocytes in response to tetanus toxoid. Sixty-seven percent of peripheral bloods and 50% of SF demonstrated positive responses to the control antigen, tetanus toxoid. In contrast, only 6 and 28%, respectively, were positive in response to type II collagen. The addition of exogenous interleukin 2 augmented responses to the tetanus toxoid, however, no such enhancement with type II collagen was noted in our patients. Our collagen was arthritogenic in experimental animals. These observations do not support the existence of T cell specificity toward type II collagen as a common mechanism for the expansion of synovial lymphocytes in RA.     

Enhancement of antigen-induced T-cell proliferation by soluble CD26/dipeptidyl peptidase IV.

The addition of a soluble recombinant CD26 (sCD26) enhanced proliferation of peripheral blood lymphocytes induced by the recall antigen tetanus toxoid. sCD26 itself did not provide a mitogenic signal and did not augment the proliferative response of T cells to other mitogenic stimuli such as phytohemagglutinin and anti-CD3. Dipeptidyl peptidase IV-negative sCD26 did not have this enhancement effect, implying a requirement for enzyme activity. It was found that there exists a large variation in the levels of human plasma sCD26/dipeptidyl peptidase IV in vivo which may regulate T-cell activity. Peripheral blood lymphocytes from individuals whose plasma sCD26 was high and responded strongly to tetanus toxoid stimulation were insensitive to the enhancing effects of exogenously added sCD26. This suggests that plasma sCD26 had modulated the responsiveness of T cells of these individuals in vivo and that the endogenous plasma sCD26 regulates immune responses by allowing antigen-specific T cells to exert a maximal response to their specific antigen.     

Granulocyte colony-stimulating factor increases CD4+ T cell counts of human immunodeficiency virus-infected patients receiving stable, highly active antiretroviral therapy: results from a randomized, placebo-controlled trial

Thirty human immunodeficiency virus (HIV)-infected patients with CD4+ T cell counts <350 cells/mm3 who had received stable, highly active antiretroviral therapy (HAART) for at least 24 weeks were randomized to receive either placebo or granulocyte colony-stimulating factor (G-CSF; 0.3 mg/mL 3 times a week) for 12 weeks. Blood samples were collected at specified time points. G-CSF treatment enhanced the total lymphocyte count (P=.002) and increased CD3+ (P=.005), CD4+ (P=.03), and CD8+ (P=.004) T cell counts as well as numbers of CD3-CD16+CD56+ NK cells (P=.001). The increases in CD4+ and CD8+ cell counts resulted from increases in CD45RO+ memory T cells and cells expressing the CD38 activation marker. Lymphocyte proliferative responses to phytohemagglutinin and Candida antigen decreased, whereas NK cell activity and plasma HIV RNA did not change during G-CSF treatment. After 24 weeks, all immune parameters had returned to baseline values. This study suggests that G-CSF treatment of HIV-infected patients receiving stable HAART increases the concentration of CD4+, CD8+, and NK cells without inducing changes in the virus load.     

Immunologic recovery after autologous blood stem cell transplantation in patients with AL-amyloidosis.

We prospectively studied absolute lymphocyte (ALC) and monocyte counts (AMC), lymphocyte subsets and proliferative in vitro responses to mitogen and antigen in 12 patients with AL-amyloidosis (AL) undergoing autologous blood stem cell transplantation (SCT) with high-dose i.v. melphalan. Myeloid and lymphoid recovery (>500 per microl) occurred in a median of 10 days post SCT. While there was a continuous decline in the number of CD4+ T cells at 3 months, ALC, AMC, B cells (CD19+), CD8+ T cells, and NK cells (CD16+/56+) returned to baseline. While T cell proliferative responses to phytohemagglutinin (PHA) remained depressed, B cell function measured by the proliferative response to staphylococcal antigen returned to baseline by 3 months. To supplement our findings, we retrospectively evaluated ALC, AMC and serum immunoglobulin levels in a separate group of patients treated with the same protocol at our institution. ALC and AMC recovery was similar to the pattern observed in the initial study group. Immunoglobulin levels remained within normal ranges at 3 and 12 months after SCT. Of 50 patients who were followed for a minimum of 1 year following SCT, seven (14%) developed shingles and one (2%) had PCP pneumonia. In conclusion, cellular immune function, reflected by absolute numbers of CD4+ T cells and PHA responsive T cell proliferation, is significantly suppressed at 3 months after SCT in patients with AL, and this post-transplant immunosuppression is associated with a low but clinically meaningful occurrence of opportunistic infections typical of T cell immunosuppression.     

Beta-endorphin modulation of lymphocyte proliferation: effects of ethanol

BACKGROUND: We have previously shown that alcohol suppresses the natural killer (NK) cell activity of splenic lymphocytes partly by reducing the secretion of opioid peptide beta-endorphin (beta-EP) and its positive influence on NK-cell cytolytic activity in rats. The inhibition of NK-cell cytolytic activity was also associated with a reduced number of NK cells after chronic ethanol administration. Hence, the possibility arises that chronic ethanol may alter NK cell proliferation, survival, or both. In this study, we investigated whether ethanol treatment for 1 to 4 weeks reduces the proliferation of other lymphocyte subsets and whether beta-EP regulates ethanol's effect on lymphocyte proliferation. METHODS: Male rats were ad libitum-fed rat chow, pair-fed with isocaloric liquid diet, or fed with ethanol-containing liquid diet for 1, 2, 3, or 4 weeks. Groups of these rats were infused with beta-EP with or without the delta-receptor antagonist naltrindol into the paraventricular nucleus of the hypothalamus. Splenocytes were isolated and used for flow cytometric analysis of the changes in the number of various lymphocyte subsets. Lymphocyte proliferation was determined by mitogen stimulation assays. RESULTS: Ethanol consumption resulted in a reduction of the number of CD161+ NK cells, CD3+ T lymphocytes, CD4+ T-helper cells, and CD8a+ cytotoxic T cells in a time-dependent fashion. Alcohol consumption also suppressed the proliferative response of lymphocyte subsets to concanavalin A, phytohemagglutinin, and lipopolysaccharide. Beta-EP promoted the lymphocytes' proliferative response to mitogens, whereas naltrindol blocked the effects of the opioid. Chronic alcohol consumption reduced the proliferative response of lymphocytes to beta-EP. CONCLUSIONS: These results suggest that chronic alcohol administration reduces immune function partly by decreasing the opioid-regulated mitogen-stimulated proliferation of lymphocyte subsets.     

Lymphocyte subpopulations in sarcoidosis: correlation with disease aetivity and duration.

We studied lymphocytes from the peripheral blood of 29 sarcoid patients to relate T- and B-cell populations with disease activity and duration. In patients with acute (less than 1 year) and chronic (greater than or equal to 9 years) active disease, the absolute lymphocyte count was reduced; the absolute number of T cells was reduced; and the proliferative response of lymphocytes to phytohemagglutinin was depressed compared with control subjects. Ten of 21 patients with active disease had 5% to 32% atypical lymphocytes. The proportion of cells bearing surface immunoglobulin (Ig) was increased in patients with active disease, but the absolute number of cells bearing surface Ig did not differ significantly from controls. However, studies using overnight in-vitro culture indicated that a large fraction of these cells bound exogenous Ig. The number of cells indentified by complement receptors was significantly reduced in patients with active disease. In contrast, patients who had complete reasolution of their disease showed no significant differences from controls in either T- or B-cell populations or in the proliferative response of their lymphocytes to phytohemagglutinin.     

Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow

Clinical studies are evaluating possible advantages of allogeneic peripheral blood stem cell transplantation (PBSCT) over bone marrow transplantation (BMT). We compared immune reconstitution after PBSCT (n = 20) and BMT (n = 20) in terms of lymphocyte subset counts and proliferative in vitro responses to mitogens and recall antigens (follow-up: 5 to 11 months posttransplant). Additionally, 10 PBSC harvests and 10 marrow harvests were analyzed for their composition of immunocompetent cells. Compared with BMT patients, PBSCT recipients had PB counts of naive (CD4+CD45RA+) and memory (CD4+CD45RO+) helper T cells and of B cells (CD19+) that were elevated (P < .003, P < .001, and P < .004, respectively) and proliferative responses to phytohemagglutinin (P < .0001), pokeweed mitogen (P < .02), Tetanus toxoid (P < .0005), and Candida (P < .004) that were increased. PBSCT recipients received a mean of 188 (range, 44 to 280) x 10(6) naive helper T cells and 169 (range, 18 to 296) x 10(5) memory helper T cells per kilogram; the corresponding numbers for BMT recipients were 11 (range, 4 to 24) and 10 (range, 1 to 22) x 10(5) cells per kilogram, respectively. The question of whether the documented improved in vitro immune competence after PBSCT is associated with a lower incidence of infectious complications in vivo still needs further study.     

Impaired natural killer cell recycling in childhood chronic neutropenia with morphological abnormalities and defective chemotaxis of neutrophils

Natural killer (NK) cell activity was measured by a 51Cr-release assay using K562 target cells in 12 neutropenic children. NK cell activity was depressed in four patients who had childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The percentage of lysis at a 40:1 effector-target ratio was 28.4% to 42.1% (P less than .001) of the normal lymphocyte value during the study period (32 to 40 months). NK cell activity was normal in the other eight children with chronic neutropenia without any of these neutrophil abnormalities: lazy leukocyte syndrome, Shwachman syndrome, or dysgammaglobulinemia type I with neutrophil defects. NK cell activity of the four patients was depressed at 5:1 to 40:1 effector-target ratios. The NK cells responded to in vitro interferon (IFN)-alpha and interleukin 2, as did normal lymphocytes, but the activated levels were still lower than those of normal lymphocytes (P less than .01). Because NK cells kill a target through recognition, binding, killing, and detaching, and they repeat this lytic sequence (ie, recycling), the localization of the NK cell defect was further analyzed in the four patients using both 51Cr- release and single cell-in-agarose assays. The patients' NK cells were normal in recognizing, binding, and killing a target but were defective in recycling; the estimated maximum recycling capacity (MRC) values in a four-hour assay were 1.8 to 2.4 (P less than .01), as compared with the normal lymphocyte value of 5.5 +/- 0.6 (mean +/- SD). The stimulation of the effector cells with 1,000 U/mL IFN-alpha did not significantly increase the estimated MRC. These results demonstrate that NK cells are defective in recycling in some type of childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The NK cell deficiency is of clinical interest in terms of its relationship to the recurrent infections, development of malignancy, and dysgranulopoiesis in the disorder.     

Immunodeficiency with defective T-cell response to interleukin 1.

Normal proliferation of T cells in vitro requires production of and response to the lymphokine interleukin 2 (IL-2). Optimal IL-2 production by T cells is dependent on the monokine interleukin 1 (IL-1). A 10-year-old male with recurrent infections and failure to thrive was evaluated for possible defects in the production and response to IL-1 and IL-2. The patient had normal levels of serum immunoglobulins and a normal distribution of circulating T-cell subsets. However, the in vitro proliferative response of his peripheral blood mononuclear cells (PBMC) to phytohemagglutinin was depressed (40% of normal) and the response of his PBMC to antigens was absent. Delayed hypersensitivity skin tests and in vitro response to tetanus toxoid remained absent despite repeated immunizations. Monocyte function in this patient was normal as judged by the following criteria: normal expression of Ia antigens (77% +), normal IL-1 production, and normal capacity to present tetanus toxoid to a maternal T-cell line specific for tetanus toxoid antigen. The abnormal phytohemagglutinin response of the patient's PBMC was corrected by the addition of exogenous IL-2. IL-2 production by the patient's phytohemagglutin-stimulated PBMC was severely deficient but was corrected by the addition of phorbol 12-myristate 13-acetate, suggesting a defective response to IL-1. T-cell blasts derived from a normal subject but not T-cell blasts derived from the patient absorbed out IL-1 activity from a preparation of purified human IL-1. These results indicate that the patient's T-cell deficiency was due to a defective T-cell response to IL-1 and suggest that IL-1 plays an important role in the in vivo immune response.     

Recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor administered in vivo after high-dose cyclophosphamide cancer chemotherapy: effect on hematopoiesis and microenvironment in human bone marrow.

The effects on bone marrow (BM) cell proliferation and differentiation of recombinant human interleukin-3 (rhIL-3) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered after high-dose (7 g/m2/d) cyclophosphamide (HD-CTX) chemotherapy were studied in nine patients with malignancies without BM involvement and in three control patients. rhIL-3 at a dose of 1 to 5 micrograms/kg/day was administered for 14 to 18 days by continuous intravenous (i.v.) infusion and rhGM-CSF was administered at a dose of 5.5 micrograms/kg/day for 14 days. Changes induced by cytokine treatment were assessed by morphoimmunohistochemical analysis of BM biopsies. Comparison was made in the cytokine-treated groups and with control patients who received HD-CTX alone. BM cellularity and the myeloid/erythroid (ME) ratio were lower in rhIL-3-treated than in rhGM-CSF-treated patients, but in both groups it was significantly higher than in the controls. The proportion of BM cells stained by PC10, a monoclonal antibody (MoAb) recognizing a proliferation-associated nuclear protein (PCNA), increased from 6.78% to 21.18% (P less than .02) after rhIL-3, and from 5% to 35.33% (P less than .001) after rhGM-CSF; no increase was observed in the control group. The frequency of CD34+ BM cells was unchanged after rhIL-3 (P = NS) and decreased after rhGM-CSF (P less than .001). In both groups, most of the PC10+ cells were represented by promyelocytes and myelocytes with no increase in blast cell numbers. rhIL-3-treated BM showed an increased number of megakaryocytes and increased proliferative activity of erythroid cells as compared with rhGM-CSF cases. BM stroma changes observed in both treated groups included endothelial cell proliferation, increased BM macrophage concentration, and increase in BM fibroblasts as detected with an anti-nerve growth factor receptor antibody. In most rhIL-3-treated cases, BM fibrosis developed after treatment. The same effect was not observed in rhGM-CSF patients.     

Inhibitory effect of granulocyte-macrophage colony-stimulating factor therapy on the generation of natural killer cells.

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy on the natural killer (NK) cell lineage in patients with aplastic anemia and myelodysplastic syndrome. Selected bone marrow (BM) cells were prepared by the elimination of nylon wool-adherent cells and mature T and NK cells from BM cells. The frequency of BM NK progenitors relative to BM cells selected was significantly decreased 4 weeks after the start of rhGM-CSF therapy (P less than .01), while the peripheral blood NK cell count and NK activity were also significantly decreased (P less than .05). A return to the pretreatment levels was seen 4 weeks after the cessation of treatment in all cases. No suppressive effect was noted in the patients who received rhG-CSF therapy. These results suggest that rhGM-CSF therapy suppresses the generation of NK cells from human BM NK progenitors.     

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.     

Effect of a thymic factor on T lymphocytes in B cell chronic lymphocytic leukemia: in vitro and in vivo studies

Abnormalities of T lymphocytes in B cell chronic lymphocytic leukemia (B-CLL) have been extensively documented by several immunologic investigations. Following recent studies pointing to the favorable effect of TP-1, a partially purified extract of calf thymus, on the T cell-mediated immunity of several diseases, including Hodgkin's disease, we have used monoclonal antibodies and the enriched T lymphocytes of 16 untreated B-CLL patients to evaluate the proportion of T cell subsets before and after the administration of TP-1. In addition, the proliferative response to phytohemagglutinin (PHA) and the helper function in a pokeweed mitogen (PWM) system were assessed. In ten cases, the effect of TP-1 was also studied in vitro by evaluating the same parameters before and after incubation of B-CLL T cells with the drug. The study demonstrated that in vivo administration of TP-1 increases significantly (P less than .001) the proportion of the defective helper/inducer T cell population (OKT4-positive cells) in B-CLL, leading to a near normal OKT4/OKT8 ratio. Furthermore, the improved phenotypic profile was accompanied by an increased proliferative response to PHA and, in particular, by a significant increase (P less than .01) of T helper capacity; this increase was, however, insufficient to enable the normalization of the serum immunoglobulin levels. The in vitro incubation of B-CLL T lymphocytes did not succeed in producing significant modifications in distribution and function.