Significant Reduction In CD4 Research Articles

T cell receptor excision circles (TRECs), CD4+, CD8+ and their CD45RO+ and CD45RA+ subpopulations in hepatitis C virus (HCV)-HIV-co-infected patients during treatment with interferon alpha plus ribavirin: analysis in a population on effective antiretroviral therapy

Interferon (IFN)-alpha induced CD4(+) T lymphopenia is a toxic effect of the treatment of chronic hepatitis C virus (HCV) in human immunodeficiency virus (HIV)-co-infected patients. To increase the knowledge about this secondary effect, we performed an analysis of the evolution of the T cell receptor excision circles (TRECs), CD4(+) and CD8(+) T cells and of their CD45RO(+) and CD45RA(+) subpopulations during the treatment of chronic hepatitis HCV with peginterferon alpha (pegIFN-alpha) + ribavirin. Twenty HCV/HIV-co-infected patients, with undetectable HIV load after highly active antiretroviral therapy (HAART), were treated with pegIFN-alpha + ribavirin. TRECs were determined using real-time polymerase chain reaction. CD4(+) and CD8(+) T cells and their CD45RO(+) and CD45RA(+) subpopulations were analysed by two-colour flow cytometry. Median baseline CD4(+) and CD8(+) T cells were 592 mm(3) and 874 mm(3), respectively. Median baseline CD45RO(+) subpopulation was 48% for CD4(+) T and 57% for CD8(+) T lymphocytes. A progressive decrease in both T cell populations, as well as of their CD45RO(+) and CD45RA(+) subpopulations, was detected, with a difference between the baseline and nadir levels approaching 50%. The evolution of T cell populations and TRECs was independent of the response to the treatment. T lymphocytes and their subpopulations returned to baseline levels at 24 weeks after the end of treatment, with the exception of the T CD4(+) CD45RA(+) subpopulation. The ratio of CD4(+) CD45RO(+)/CD4(+) CD45RA(+) increased from 0.89 (baseline) to 1.44 (24 weeks after the end of the therapy). TRECs/ml did not return to the basal values. In conclusion, a significant reduction of CD4(+) and CD8(+) T cells, and of their CD45RA(+) and CD45RO(+) subpopulations, in HIV/HCV co-infected patients treated with pegIFN-alpha was observed. Both subpopulations increased after the suppression of treatment, but the CD4(+) CD45RA subpopulation did not reach the basal levels as a consequence, at least in part, of a decrease in thymic production.

T-LYMPHOCYTE PROFILES IN FIV-INFECTED WILD LIONS AND PUMAS REVEAL CD4 DEPLETION

Feline immunodeficiency virus (FIV) is a lentivirus related to human immunodeficiency virus (HIV) that causes feline AIDS in the domestic cat (Felis catus). Serological surveys indicate that at least 25 other species of cat possess antibodies that cross-react with domestic cat FIV. Most infected nondomestic cat species are without major symptoms of disease. Long-term studies of FIV genome variation and pathogenesis reveal patterns consistent with coadaptation of virus and host in free-ranging FIV-Ple-infected African lions (Panthera leo) and FIV-Pco-infected pumas (Puma concolor) populations. This report examined correlates of immunodeficiency in wild and captive lions and pumas by quantifying CD5(+), CD4(+), and CD8(+) T-cell subsets. Free-ranging FIV-Ple-infected lions had immunofluorescence flow cytometry (IFC) profiles marked by a dramatic decline in CD4(+) subsets, a reduction of the CD4(+)/CD8(+) ratio, reduction of CD8(+)beta(high) cells, and expansion of the CD8(+)beta(low) subset relative to uninfected lions. An overall significant depletion in CD5(+) T-cells in seropositive lions was linked with a compensatory increase in total CD5(-) lymphocytes. The IFC profiles were altered significantly in 50% of the seropositive individuals examined. The FIV-Pco-infected pumas had a more generalized response of lymphopenia expressed as a significant decline in total lymphocytes, CD5(+) T-cells, and CD5(-) lymphocytes as well as a significant reduction in CD4(+) T-cells. Like lions, seropositive pumas had a significant decline in CD8(+)beta(high) cells but differed by not having compensatory expansion of CD8(+)beta(low) cells relative to controls. Results from FIV-infected lions and pumas parallel human and Asian monkey CD4(+) diminution in HIV and SIV infection, respectively, and suggest there may be unrecognized immunological consequences of FIV infection in these two species of large cats.

Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity

Myeloid suppressor (Gr-1(+)/CD11b(+)) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8(+) T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist. The effect of the chemotherapy drug gemcitabine on the number of (Gr-1(+)/CD11b(+)) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-beta. This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4(+) T cells, CD8(+) T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8(+) T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-beta markedly enhanced antitumor efficacy. These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.

Decreased number of granzyme B+ activated CD8+ cytotoxic T lymphocytes in the inflammatory background of HIV-associated Hodgkin’s lymphoma

This study aimed to assess the differences in the cellular composition of the inflammatory reactive background around tumoral cells of classical Hodgkin's lymphomas (cHL) inside and outside the HIV settings. This retrospective study evaluates the infiltrating T lymphocytes (CD4 and CD8), natural killer cells (CD57+ cells), and more especially cytotoxic cells [granzyme B (GrB) and TIA-1+ cells] in the background of 99 EBV+ cHL. Sections from paraffin-embedded tumor samples from nine HIV-infected cHL patients were immunostained, using standard immunohistochemical protocols and were compared to a control group of 90 HIV-noninfected cHL patients. Our clinical and histological data indicate that HIV-infected cHL patients present a higher frequency of mixed cellularity (MC) histological subtypes, more advanced disease stages, a poor response to treatment, and a poor overall survival compared to control patients. In controls, CD4/CD8 and GrB/TIA-1 ratios were determined as 2:1 and 1:2, respectively. The inflammatory infiltrate of HIV-infected patients had a significant reduction of CD4+ T lymphocytes (CD4/CD8 ratio 1:23), a decrease in infiltrating GrB+ cells (activated cytotoxic cells) and an increase in infiltrating TIA+ T cells (mainly nonactivated cytotoxic cells) in these patients (GrB/TIA-1 ratio 1:12). In conclusion, this study highlights an important intratumoral loss of CD4+ T cells (striking inversion in the CD4/CD8 ratio) and a decrease in intratumoral activated cytotoxic T lymphocytes in HIV-associated cHL patients. Further studies are required to confirm these results and to determine the role of these findings on the antitumoral immune response observed in HIV-associated cHL.

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial

Systemically administered sirolimus has demonstrated efficacy in psoriasis in a multicentre European study. To determine the efficacy and safety of topically applied sirolimus in treating psoriasis. In vitro studies were followed by a pilot study designed to determine if sirolimus penetrates human skin, and by a randomized, double-blind, left-right comparative, dose-ranging study consisting of treatment with 2.2% sirolimus for 6 weeks and 8% sirolimus for an additional 6 weeks in 24 patients with stable, chronic plaque psoriasis. The primary outcome measure was clinical score. Secondary measures were ultrasound plaque thickness, plaque erythema, and computerized image analysis of immunohistochemical stains for immunocytes and proliferating cells. Pharmacokinetics and blood chemistry monitoring for safety were also performed. A significant reduction in the clinical score (P = 0.03) (mean score 9.1 following sirolimus vs. 11.2 in control) was achieved with topical sirolimus. Measurements of plaque thickness and erythema did not show significant improvement with treatment. Computerized image analysis of biopsies showed a significant reduction in CD4+ cells (P = 0.0054) and proliferating cells (stained by Ki-67) in the epidermis (P = 0.0153) with sirolimus treatment compared with control. Topically applied sirolimus penetrates normal skin and may have some antipsoriatic and immunosuppressive activity.

High incidence of spontaneous autoimmune thyroiditis in immunocompetent self-reactive human T cell receptor transgenic mice

Autoantigen-specific TCR transgenic mice allow us to assess the role of T cells in autoimmunity. We have recently generated humanized TAZ10 transgenic mice expressing the human TCR specific for the immunodominant epitope of thyroid peroxidase (TPO). We have shown that these transgenic mice do not undergo tolerance in vivo and that on Rag deficient background they are susceptible to spontaneous autoimmune thyroiditis. Here we show that, in contrast to other transgenic models of autoimmunity, almost all TCR + Rag1 + (T+R+) T cells are activated in vivo leading to the development of spontaneous autoimmune thyroiditis. In these mice, disease is also accompanied by a significant reduction of CD4+CD25 hi regulatory T cells. These data indicate that the pathogenic activity of the self-reactive TCR can circumvent the regulatory function operated by the non-transgenic T cells that are normally present in T+R+ mice, leading to autoimmunity.

Use of a microgravity organ culture dish system to demonstrate the signal dampening effects of modeled microgravity during T cell development

Recently, we have shown that exposure of fetal thymus organ cultures (FTOC) to modeled microgravity (MMG) using a clinostat with a microgravity organ culture dish system (MOCDS) blocks T cell development in a manner independent of steroid stress hormones present in vivo. In this study, we describe the development of the MOCDS system, as well as its use in attempting to understand the mechanism by which T cell development is inhibited in MMG. We show that after MMG exposure FTOC exhibited a significant reduction in CD4 +CD8 + double positive (DP) cell production, but those DP cells which remained expressed higher levels of the T cell receptor (TCR) associated molecule, CD3. Interestingly, CD4 −CD8 − double negative (DN) cells expressed lower levels of CD3 on their surface. DN, as well as immature single positive (ISP) cells, also expressed reduced levels of the IL-7 receptor α chain (CD127). These changes in CD3 and CD127 expression were concomitantly associated with an increased production of tumor necrosis factor (TNF)-α. We were also able to show that addition of an exogenous signal (anti-CD3ε monoclonal antibody) to these cultures effectively mitigated the MMG-induced effects, suggesting that MMG-exposure causes a signal dampening effect on developing thymocytes.

Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery.

Rapamycin (Rapa) is an immunosuppressant that is used in patients and animal models to control allograft rejection. Its mechanisms of action are not fully understood. In this article, the authors have investigated the effects of therapeutic doses of Rapa on both thymic and peripheral T-cell populations in the adult rat. The therapeutic dosage of Rapa was optimized using cardiac transplantation between LEW and DA rats. Thymic morphology was assessed by hematoxylin-eosin staining. Flow cytometric analysis was performed to analyze T-cell phenotype and apoptosis. T-cell receptor (TCR)-mediated T-cell responsiveness was evaluated by 3[H]-thymidine deoxyribose incorporation. Rapa induced atrophy in the thymus but not in peripheral lymphoid organs. Moreover, fibrosis occurred in thymus that was long-lasting after Rapa withdrawal. In animals treated with Rapa, there was a significant reduction in CD4+CD8+ thymocytes caused by accelerated apoptosis, whereas CD4-CD8-, CD4+CD8-, and CD8+CD4- populations remained unaffected. In contrast, the cellularity of the periphery lymphoid organs was not altered. Within the CD4+ thymocyte population, CD4+CD25+ thymocytes were resistant to Rapa-accelerated apoptosis, and in the periphery, the ratio of CD4+CD25+ to CD4+CD25- T cells was increased. Notably, the peripheral CD4+CD25+ T cells were hyporesponsive to TCR-mediated activation. The resistance of the peripheral CD4+CD25+ T cells to Rapa treatment might contribute to its immunosuppressive action. The long-term effects of Rapa on thymus atrophy and thymocyte development requires consideration with respect to its clinical application.

Interferon-α significantly reduces cerebrospinal fluid CD4 cell subsets in HAM/TSP

We, for the first time, analyzed T cell and natural killer (NK) cell subsets in the cerebrospinal fluid (CSF) in nine patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) treated with interferon-α (IFN-α). The CD4/CD8 ratio in CSF was significantly lower after the therapy, which is mainly attributable to the significant reduction in CD4+ cells, especially CD25+CD4 and CD45RO+CD4 cell subsets. Meanwhile, NK, natural T and NKT cell subsets in the CSF remained unchanged. There was no CSF lymphocyte subset significantly associated with the clinical efficacy of IFN-α in this small-scale study, and more patients should be analyzed to ascertain the link.

Impairment of antigen-specific cellular immune responses under simulated microgravity conditions.

Microgravity has been implicated to play a role in the observed immune dysfunction of astronauts and cosmonauts after either short-term or long-term space travel. These reports, together with studies describing increased levels of microorganisms in the space cabin environment suggest potential risk for in-flight incidences of infectious diseases. In order to understand the mechanism underlying these immune defects, it is important to have a ground-based model that would reliably mimic the effects of microgravity on antigen-specific immune function. We tested the utility of the rotating wall vessel (RWV) technology developed at NASA as a model system because in the RWV the culture medium and the cells rotate synchronously with the vessel, thereby creating simulated microgravity conditions. We compared the RWV to the conventional tissue culture flask (T-flask), for culturing immune precursor cells with cytotoxic T lymphocyte (CTL) activity against synthetic viral peptides. We observed a significant loss of antigen-specific CTL activity in RWV cultures, but not in those from the T-flask, irrespective of the peptide immunogen used for inducing the primary immune response in different mouse strains. Loss of CTL activity in RWV cultures coincided with a significant reduction in CD8+ cells as well as CD4+ cells and DEC205+ dendritic cells, suggesting adverse effects of RWV culturing on both the effector and accessory cells for the loss of antigen-specific CTL function. These results provide a strong parallel to the reported defects in cell-mediated immunity during space travel and strongly support the utility of the RWV technology as an effective ground-based model for identifying key steps in immune cell dysfunction related to microgravity.

CYCLOSPORIN A IN PATIENTS AFFECTED BY CHRONIC IDIOPATHIC URTICARIA: A THERAPEUTIC ALTERNATIVE

Chronic Idiopathic Urticaria (CIU) is a cutaneous disorder for which there is no identifiable specific etiologic agent. Some recent evidences suggest that CIU might be an autoimmune disease. We analyzed immunological features occurring in CIU and evaluated effectiveness and tolerance of Cyclosporin A (CsA) treatment in patients unresponsive to antihistaminic treatment.Twenty patients with CIU were recruited after a selective diagnostic protocol and were divided into two groups. CsA was prescribed for group 1 and Prednisone for group 2 as control, for 8 weeks. Before and after the therapy we performed on all patients immunological studies.For all patients symptoms disappeared after a few days of therapy. Before therapy all patients showed activated B cells (CD19+CD23+ cells) and among B CD19+ cells, about 20% were CD5+ (cells that synthesize natural autoantibodies). After treatment with Prednisone in group 2, a significant reduction of CD4+ lymphocytes (p + 0,01) was observed.Our findings might support the CIU autoimmune pathogenetic hypothesis. The clinical remission in the CsA-treated group confirmed the therapeutic effectiveness of this therapy in antihistaminic unresponsive CIU and, at dosage used, side effects were rare, mild and reversible. Thus, CsA might be a good therapeutic alternative in CIU patients unresponsive to conventional treatments.

Class II transactivator: mastering the art of major histocompatibility complex expression.

Major histocompatibility complex (MHC) class II molecules are the predominant presenters of exogenous antigens to T helper cells (reviewed in references 21, 77, and 99). These key molecules are critical for numerous aspects of immune function, including T-cell selection, tolerance induction, antibody production, T-cell-mediated immunity, and the inflammatory response. As principal mediators of transplant rejection, these molecules are often common targets for immune therapies to prevent the rejection of grafted tissues. Class II MHC is implicated as a contributing factor in a host of diseases ranging from rheumatoid arthritis and diabetes to Alzheimer's disease and multiple sclerosis. Constitutive expression of class II MHC is restricted to “professional” antigen-presenting cells but can be induced on various tissues by gamma interferon (IFN-γ). In humans, a congenital lack of both constitutive and inducible class II results in a profound and generally fatal immunodeficiency (type II bare lymphocyte syndrome [BLS]) (7, 29, 45, 61, 67, 75, 112) marked by a significant reduction of CD4+ T cells. Early molecular forays addressing BLS revealed that the genes encoding class II MHC were not defective. Instead, the defect lay in transcription factors controlling class II MHC gene expression. BLS thus became the first disease known to be caused by defective or absent transcription factors. The availability of patient-derived cell lines with class II MHC transcription defects provided a unique tool of nature to identify the requisite transcription factors. Transcriptional regulation of class II MHC expression is complex. Class II MHC and related promoters are characterized by the presence of conserved W (or S), X, and Y boxes (Fig. ​(Fig.1)1) (reviewed in references 10, 67, and 75). The X element is bipartite. The upstream X1 region is recognized by RFX, a trimeric complex of RFX family members including RFX5, RFXANK (RFX-B), and RFXAP (32, 74, 87, 117). The downstream X2 box is bound by X2BP (NF-X2), a complex comprising CREB, and an unidentified 120-kDa protein (83, 84). Another trimeric complex, NF-Y (CBF), which is highly conserved in eukaryotes, binds the Y box (69, 71, 146; reviewed in reference 70). A number of factors interacting with the W box have been described, including the RFX complex (26, 48, 120). The factors involved in X and Y box binding are ubiquitous and expressed constitutively yet fail to account for either constitutive or IFN-γ-inducible class II MHC expression. Somatic cell fusions using BLS patient-derived cells allowed the definition of complementation groups, with each group containing a defect in a single genetic locus. This type of analysis revealed a crucial locus, aIr-1, which in all likelihood encodes the class II transactivator (CIITA), which explained the lack of class II transcription in BLS complementation group A (1, 118). Group A cells express the requisite X and Y binding proteins but fail to transcribe class II. CIITA expression appears to be a nearly absolute requisite for expression of class II MHC, whether constitutive or inducible (17, 19, 23, 47, 85, 103, 114, 118, 119). A number of class II MHC-related genes including genes encoding HLA-DM (H-2M in mice) and invariant chain (Ii), with promoters similar to those for classical class II genes, are also regulated by CIITA (17, 18, 22, 23, 50, 137). CIITA can also upregulate expression of class I MHC genes and beta-2-microglobulin (β2m) through effects at site α in addition to X- and Y-like sequences in the promoters for these genes (40, 72, 104). These initial observations have led to the view that CIITA is a master, or global, regulator for expression of class II MHC and related genes. FIG. 1 Organization of W, X, Y, and other motifs in the promoters of class II MHC and related genes. Genes coding for class II MHC and related proteins contain well conserved W, X, and Y boxes, the presence of which correlates with transcriptional regulation ... Since the discovery of CIITA, numerous primary articles and several reviews on its role in regulating the class II MHC have been published. In this review, we will discuss the molecular structure of this novel protein, its mechanism of function, and its biologic and clinical relevance, which is broad.

Administration of mAb Against αEβ7 Prevents and Ameliorates Immunization-Induced Colitis in IL-2−/− Mice

Abstract We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2−/− mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn’s disease. The integrin αEβ7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of αEβ7 in colitis, we administered a mAb against αEβ7 to IL-2−/− mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0–2 vs 3–4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 ± 0.6 × 107 vs 1.2 ± 0.2 × 107; p < 0.05). Similarly, functional studies revealed that IFN-γ production by lamina propria lymphocytes isolated from IL-2−/− TNP-OVA-immunized mice treated with anti-αEβ7 was significantly lower than in untreated IL-2−/− TNP-OVA-immunized mice. In contrast, IFN-γ production by splenic cells isolated from treated IL-2−/− TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2−/− mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after αEβ7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing αEβ7.

Leukocyte Filtration Does Not Affect Lymphocyte Subpopulations and NK Cell Function in Recipients of Blood Transfusions

Background and objectives: The possible immunosuppressive action of blood transfusion has aroused great interest recently, particularly with respect to its effects on tumor growth and recurrence rate of malignant disease. Materials and methods: The effect of blood transfusion on lymphocyte subpopulations and NK cell function preoperatively and 6 months postoperatively was studied in 129 patients treated with elective surgery for colorectal malignancy. Forty-two patients (33%) received blood transfusions, 21 of them randomly allocated to receive leukocyte-depleted blood products. Investigation was by means of conventional laboratory methods. Results: In 21 patients receiving a median of 3 units of non-leukocyte-depleted blood products (NLD), a significant reduction in CD4+ lymphocytes (44% vs. 40%, p < 0.01) occurred. In contrast, no significant changes in CD4+ lymphocytes were observed in the 21 patients transfused with leukocyte-depleted blood products (LD). However, with respect to lymphocyte subpopulations and NK cell function, differences between the NLD and LD groups were not significant. There was a marginal decrease in HLA-DR+ lymphocytes in the NLD patients without a history of previous transfusion. Conclusions: There seems to be no major change in lymphocyte subpopulations and NK cell function 6 months after blood transfusion. Thus we cannot confirm our previous findings of a reduced number of CD20+ cells after blood transfusion.

Leukocyte Filtration Does Not Affect Lymphocyte Subpopulations and NK Cell Function in Recipients of Blood Transfusions

The possible immunosuppressive action of blood transfusion has aroused great interest recently, particularly with respect to its effects on tumor growth and recurrence rate of malignant disease. The effect of blood transfusion on lymphocyte subpopulations and NK cell function preoperatively and 6 months postoperatively was studied in 129 patients treated with elective surgery for colorectal malignancy. Forty-two patients (33%) received blood transfusions, 21 of them randomly allocated to receive leukocyte-depleted blood products. Investigation was by means of conventional laboratory methods. In 21 patients receiving a median of 3 units of non-leukocyte-depleted blood products (NLD), a significant reduction in CD4+ lymphocytes (44% vs. 40%, p < 0.01) occurred. In contrast, no significant changes in CD4+ lymphocytes were observed in the 21 patients transfused with leukocyte-depleted blood products (LD). However, with respect to lymphocyte subpopulations and NK cell function, differences between the NLD and LD groups were not significant. There was a marginal decrease in HLA-DR+ lymphocytes in the NLD patients without a history of previous transfusion. There seems to be no major change in lymphocyte subpopulations and NK cell function 6 months after blood transfusion. Thus we cannot confirm our previous findings of a reduced number of CD20+ cells after blood transfusion.

Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virus-infected individuals

The immune responses to Mycobacterium leprae and other mycobacterial antigens were studied in 11 leprosy patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection. Three patients manifested borderline lepromatous leprosy, and eight patients had borderline tuberculoid (BT) leprosy. Despite the low CD4+ T-cell count in the peripheral blood, no histologic or phenotypic change in the cellular infiltrate in either the lepromatous or tuberculoid lesions was observed when compared with HIV-1-negative patients. Lepromatous lesions contained heavily parasitized macrophages and few CD8+ T cells. Lesions from the patients with BT leprosy showed extensive CD4+ T-cell infiltration despite a significant reduction in CD4+ T-cell counts in the peripheral blood. No acid-fast bacilli were detected in the tuberculoid lesions. HIV-1 infection did not alter the lack of response in lepromatous leprosy to M. leprae antigens either in vitro or in vivo. In contrast, the skin test response to M. leprae antigens as well as the in vitro lymphoproliferative responses to mycobacterial antigens that are usually seen in patients with tuberculoid leprosy were abrogated in the BT HIV-1+ patients. However, production of gamma interferon in response to the same stimuli was preserved in most of the patients. Analysis of cytokine gene expression showed activation of additional cytokine genes in the unstimulated peripheral blood cells of patients with both leprosy and HIV-1 infections as compared with cells from patients with leprosy alone. These results suggest that granuloma formation in leprosy can be independent of the impaired CD4+ T-cell response of the HIV-1 infection. Furthermore, in HIV-1+ individuals with M. leprae infection, activation of cytokine genes is observed even when the circulating CD4+ T-cell count is significantly reduced.

Changes in peripheral blood lymphocyte subset frequencies in myasthenia gravis patients are related to immunosuppression.

Surface antigens on peripheral blood lymphocytes from myasthenia gravis patients were investigated. The expression of DR+ and CD8+/DR+ T lymphocytes was increased and the expression of CD4+ T cells reduced. Neither thymectomy, clinical condition nor anti-acetylcholine receptor antibody titre correlated with any of the changes in peripheral blood lymphocyte subsets observed. However, immunosuppressive therapy correlated with the significant reduction in CD4+ and CD2+/CD4+ T cells in these patients.

Thymopentin in Sézary syndrome.

Response to the treatment of Sézary syndrome (a cutaneous T-cell lymphoma) is poor. Since patients with this syndrome are elderly, aggressive chemotherapy is poorly tolerated and deep immunodepression may result in fatal opportunistic infections. Immunomodulating therapy seems important in the management of Sézary syndrome. In a pilot study, we assessed the efficacy of thymopentin (TP-5), a synthetic pentapeptide, correlating clinical responses to the histologic and immunologic effects of the drug. Twenty Sézary syndrome patients received 50 mg TP-5 intravenously three times a week for a mean time of 16.3 months. Skin and lymph node histology and immunohistochemistry, circulating lymphoid cell subpopulations, and soluble interleukin-2 receptors were evaluated before treatment and during follow-up. Eight complete remissions and seven partial remissions were obtained (75%). No change was observed in three patients, and disease progression was observed in two patients. The median duration of response was 22 months (complete remission, 25.5 months; partial remission, 14 months). Four-year survival probability was 53.9%. The responses were obtained when circulating Sézary cells were less than 2600/mm3. A significant reduction of CD4+ cells paralleled a CD8+ cell increase. An increase in NK cells (CD16+ and CD56+) was accompanied by significantly longer survival. Serum soluble interleukin-2 receptor values were a useful monitor of the clinical course and treatment. Loss of epidermotropism, reduction of Langherhans' cells, and HLA-DR+ keratinocytes were found. TP-5 is a potentially useful agent in the treatment of a subgroup of patients with Sézary syndrome; its activity seems to be mediated by an effect on a normal NK cell-like subpopulation. The biological and clinical role of this therapy in combination with conventional treatments will be the subject of future investigations.

Increased Antiplatelet T Helper Lymphocyte Reactivity in Patients With Autoimmune Thrombocytopenia

AbstractChronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P < .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL-2) (P < .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P < .001) and a concomitant increase in CD3DR+ activated T cells (P < .001) and CD19+ B cells (P < .05). These data indicate that CD44 T-helper cells from patients with ATP are stimulated by normal platelet anti-gents) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.

Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia

Chronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P less than .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL- 2) (P less than .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P less than .001) and a concomitant increase in CD3+DR+ activated T cells (P less than .001) and CD19+ B cells (P less than .05). These data indicate that CD4+ T- helper cells from patients with ATP are stimulated by normal platelet antigen(s) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.