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A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period. The patient did not develop infectious complications during the procedure. At 35 months of follow-up, his CD4+ T cell count was 1019 cells per microliter. Non-myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.

Despite the well known interrelationship between the CD2- and CD3-mediated signal transduction pathways, it is not well established whether the CD2 surface expression can be regulated by triggering of TCR/CD3 complex. In this study we show that the stimulation of human PBMC with the Cris-7 (CD3) mAb, both in soluble and particulate form, results in hyperexpression of the CD2 surface Ag, as assessed by immunofluorescence and semi-quantitative immunoprecipitation assays. Similar effects on CD2 surface expression were obtained when different CD3 mAb (OKT3, RW2-8C8 and Leu-4) were tested. The CD3-mediated CD2 up-regulation was suppressed by cycloheximide and actinomycin D, indicating that it requires de novo protein and RNA synthesis. In agreement with this, increased CD2 RNA levels were observed after 3 h of stimulation, reaching a plateau at 24 h that was maintained for 72 h. The CD2 up-regulation was concomitant to other CD3-induced activation-related events such as induction of surface CD25 and CD71 and high RNA levels for c-myc, IL-2R alpha- and beta-chains, CD71, and IFN-gamma. CD2 up-regulation appeared to be elicited by a protein kinase C-dependent mechanism because it was abrogated by staurosporine, a potent protein kinase C inhibitor. Moreover, IL-2-dependent events may also help in enhancing CD2 hyper-expression because it was only partially inhibitable by cyclosporine, dexamethasone, or Mar-108 (CD25) mAb. In conclusion, our data suggest that CD2 up-regulation can be a relevant event in T cell activation triggered by the physiologic engagement of the TCR/CD3 complex.

An ELISA test was performed in order to measure the serum levels of secretory IgA (sIgA) in 51 patients with ankylosing spondylitis (AS) and 30 healthy controls. Raised values of sIgA were found in AS patients compared to controls. Patients with active disease, defined by clinical criteria, showed a significant elevation of serum sIgA compared to healthy controls (p = 0.03) or to patients with inactive disease (p = 0.02). A positive correlation between total serum IgA and sIgA was found (p = 0.001). Our findings further support the role of the mucosal stimulation in the pathogenesis of AS.

To assess the effectiveness of two triple antiretroviral combinations (2 nucleoside reverse transcriptase inhibitors [NRTIs] + 1 protease inhibitors [PI] vs. 2 NRTIs + 1 nonnucleoside reverse transcriptase inhibitor [NNRTI]) to correct T-cell subsets abnormalities and to restore immune functions in asymptomatic antiretroviral-naive HIV-1-infected patients with a baseline CD4 T-cell counts500/mm3 and plasma viral load5000 copies/mL.Twenty randomized patients from 2 cohort studies receiving either stavudine (d4T) + lamivudine (3TC) + indinavir (n = 9), or d4T + didanosine (ddI) + nevirapine (NVP) (n = 11) were studied. Viral load, T-cell subsets and T-cell functions were analyzed at baseline and after 1 year of treatment.After 1 year of follow-up, the PI regimen was significantly more effective in reducing plasma and lymphoid tissue VL to undetectable levels. A significant increase in CD4+ T cells was observed in patients treated with PI (p =.0007) compared with those treated with NVP. Percentages of CD8+ T-cells and of activated CD8+ T-cells (CD38+ and DR+ as well as memory CD45RO+) decreased in all patients. An increase of the CD28+ subset of CD8+ T-cells also occurred in both groups of treatment. Naive T cells were maintained in the CD4+ subset and augmented in the CD8+ subset in all patients. In both PI and NVP groups, memory CD4+ T-cells increased significantly (p =.03). Peripheral blood mononuclear cell responsiveness to polyclonal stimuli and to tetanus toxoid and cytomegalovirus (CMV) antigen was similar in both groups of treatment. HIV-infected patients treated for 1 year with both triple combinations lacked significant T-cell responsiveness to HIV-1 proteins.These data suggest that immune reconstitution achieved after 1 year of therapy with PI-containing or PI-sparing regimens is similar, despite the higher effectiveness of PI-containing regimens in reducing viral load. Additional therapeutic approaches should be designed to restore HIV-1-specific responses.

Background: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. Objective: To examine postulated associations of genetic alleles with HIV-1 disease progression. Design: Meta-analysis of individual-patient data. Setting: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. Patients: Patients with HIV-1 infection who were of European or African descent. Measurements: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. Results: Both the CCR5-Δ32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74 P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log10 copies/mL and -0.14 log10 copies/mL P < 0.05 for both). Having the CCR5-Δ32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3′A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97 P < 0.5 for all). Conclusions: The CCR5-Δ32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3′A homozygosity carried no such protection. 135 782 795 Cited By :238

Anti-Sia-lb (formerly anti-Gd) cold agglutinins (CAs) recognize sialylated carbohydrates on both adult and neonate red blood cells (RBCs). RBC CA activity inhibition experiments reported here indicate that the domain NeuNAc alpha2-3Gal, as found in sialyllactose, synthetic sialyl(s) Lewis(Le)(x) and sLe(a), sialyllactosamine, sialyl-fucosyllactose, and nonfucosylated sLe(a), constitutes the minimal epitope for these CAs, implicating that these autoantibodies could be able to bind this domain in sLe(x) and sLe(a) and related carbohydrates expressed on nucleated cells and in soluble cancer-related mucins. The following data obtained with the previously characterized monoclonal IgMk anti-Sia-lb CA, GAS, show that this is the case. GAS epitope expression among leukocytes that lack sLe(a) parallels that of sLe(x) determinant as detected by mouse monoclonal antibodies (MoAbs), especially MoAb KM-93. It is also found on epithelial malignant cells bearing both sLe(x) and sLe(a). GAS epitope on these nucleated cells, (1) like that present on RBC, is abolished by sialidase, unaffected by proteases, and inhibited by sialyllactose; and (2) is overlapping and/or proximal to that recognized by anti-sLe(x) MoAb, CSLEX-1, and KM-93. Moreover, CAGAS binds soluble cancer-associated mucins bearing sLe(x) and sLe(a) determinants. This binding is inhibited by sialyllactose and these mucins inhibit the RBC CA activity of CAGAS. The possible significance of anti-Sia-lb (anti-Gd) CAs as autoantibodies directed to carbohydrate ligands of host adhesion molecules that might be receptors of microbial adhesins of some CA-inducing pathogens is discussed.

As an approach to study the mechanisms regulating the surface expression of CD5 antigen on T cells, the effects of agents that activate different lymphocyte functions were examined. Active tumour promoter agents (TPA), such as phorbol ester analogues [phorbol 12-myristate 13-acetate (PMA), phorbol 12, 13-dibutyrate (PBu2)] and mezerein, were able to increase the expression of CD5 on the cell surface of all T-cell lines), as deduced from immunofluorescence and immunoprecipitation analysis. The TPA-induced CD5 up-regulation occurred in a dose-and time-dependent manner and was dependent on protein and RNA synthesis. From the other stimuli tested, the T-cell mitogens [phytohaemagglutinin (PHA) and concanavalin A (Con A)], as well as monoclonal antibodies (mAb) against the CD3 complex, also increased CD5 expression, although to a lesser degree. In all cases the increments were shown to be dependent on protein kinase C (PKC), as evidenced by their inhibition with staurosporine, a potent inhibitor of PKC activation. These data suggest that CD5 up-regulation on T cells can be a physiological event that depends on PKC activation.

Individual leukaemic B cells of chronic lymphocytic leukaemia (CLL) do not proliferate to B cell growth factor (BCGF) or interleukin 2 (IL-2) when co-stimulated with immunoglobulin (Ig) ligands. To exclude possible defective signalling via surface Ig (sIg), phorbol myristate acetate (PMA) plus calcium ionophore (A23187) were used to activate purified CLL B cells and compared with staphylococcal protein A coupled to sepharose beads (Seph-PA). RNA synthesis and phenotypic changes after PMA plus A23187 stimulation indicate that CLL B cells from (10) different individuals are similarly able to undergo the G0 to the G1 phase transition and express surface activation antigens. In contrast, they are variable in the capacity to show DNA synthesis, which occurred in only six out of 10 cases. Even in the presence of BCGF (10%, v/v) or IL-2 (50 U/ml) four out of nine CLL B cells activated with PMA plus A23187 or PMA alone were still unable to proliferate although they were induced to express CD23, 4F2, CD25 and OKT9 antigens by PMA plus A23187. However, PMA plus A23187 induced IgM secretion which increased further in response to IL-2 even in the absence of DNA synthesis. Moreover, in other CLL B cell populations, the unresponsiveness to growth factors upon co-stimulation with Ig ligands (Seph-PA) may simply reflect a defective signalling via sIg cross-linking which can be circumvented by PMA plus A23187 stimulation. Recombinant Interferon-gamma (50 U/ml) failed to affect DNA synthesis and IgM secretion.

Correspondence: SIR, We read with interest the recent paper by Sanders et al on the correlation of immunoglobulin and C reactive protein (CRP) levels in 22 patients with ankylosing spondylitis (AS) and 20 patients with rheumatoid arthritis (RA).' The authors found that IgA serum levels, though raised in AS, do not correlate with CRP levels as they do in RA, suggesting that the mechanism of increase of IgA in the two diseases may be different. They conclude that production of IgA in AS is unrelated to the stimulation of acute phase reactants, reflecting a specific mucosal immune stimulation, possibly in the gut. Thus IgA may be a marker of the pathogenesis of AS.