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Objective: To evaluate treatment-mediated changes in HIV-1 RNA and CD3 count as prognostic markers and surrogate end points for disease progression (AIDS/death). Methods: Data from 13,045 subjects in all 16 randomized trials comparing nucleoside analogue reverse transcriptase inhibitors and having HIV-1 RNA measurements at 24 weeks were obtained. A total of 3146 subjects had HIV-1 RNA and CD3 count determinations at 24 weeks after starting treatment. Results: At Week 24, the percentage of subjects experiencing an HIV-1 RNA decrease of >1 log(10) copies/ml or a CD4 count increase of >33% was similar (22% vs 25%). Changes in both markers at Week 24 mere significant independent predictors of AIDS/death: across trials, the average reduction in hazard was 51% per 1 log(10) HIV-1 RNA copies/ml decrease (95% confidence interval: 41%, 59%) and 20% per 33% CD4 count increase (17%, 24%). In univariate analyses, the hazard ratio for AIDS/death in randomized treatment comparisons was significantly associated with differences between treatments in mean area under the curve of HIV-1 RNA changes to Weeks 8 and 24 (AUCMB) and mean CD3 change at Week 24, but, in multivariate analysis, only mean CD4 change was significant. Conclusions: Change in HIV-1 RNA, particularly using AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term changes in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death.

Summary Background To assess the effects of zidovudine, didanosine, and zalcitabine on HIV disease progression and survival, we undertook meta-analyses of individual patient data and tabular data from all randomised trials that compared these agents. Methods Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alone. The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event). Flndings In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p Interpretation Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, zalcitabine delayed both disease progression and death, at least when added to zidovudine. The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors.

Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients.94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56.CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups.Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

A number of antibody activities of human monoclonal immunoglobulins (Ig) have been described and knowledge in this field has progressed since we reviewed it 20 years ago (Seligmann and Brouet 1973). In this presentation, we wish to update the current findings and concepts, summarize our data on monoclonal autoantibodies to myelin-associated glycoprotein (MAG), and emphasize their relevance to the problem of the origin of autoantibodies.

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets50 x 10(9)/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18 x 10(9)/L to 223 x 10(9)/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 x 10(6)/L to 725 x 10(6)/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [CI], 15% to 31%) and the AIDS-free survival was 69% (95% CI, 61% to 77%). To investigate the potential impact of splenectomy, a Cox's multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P = 0.23), survival (P = 0.64) and AIDS-free survival (P = 0.72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.

We report the results of peripheral blood stem cell (PBSC) collection performed after priming with a semi-intensive CHOP regimen in 70 patients with aggressive multiple myeloma (MM). Forty-one of the 44 previously untreated patients compared to 17 of the 26 patients with a refractory disease yielded stem cells enough for autotransplantation. Phenotypic and genotypic studies of collected mononuclear cells, even performed after depletion of monocytes and/or of T lymphocytes, did not reveal contamination by tumor plasma cells or clonal B cell precursors in any studied case. Forty-eight of the 58 patients with successful PBSC collection have been presently treated by high dose therapy followed by autologous blood stem cell transplantation (ABSCT). Among the 43 patients who received a regimen including total body irradiation, four died within six months after the autograft. All remainders responded and most often achieved an impressive tumor mass reduction. Ten relapsed and four died from disease progression. Nine to 70 months (median: 35 months) after blood stem cell collection, 29 patients are either in apparent complete remission or with a state of stable residual disease, most often minimal. Blood stem cell autograft was successful in all evaluable patients and the kinetic of hematologic recovery was roughly related to the amount of reinfused CFU-GM (2.1 to 50 x 10(4)/kg). Median delays for granulocytes greater than 500/mm3 and platelets greater than 25,000/mm3 were 15 days and 20 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Infection with the human immunodeficiency viruses results in a profound immunosuppression responsible for most of the clinical features of AIDS. The virus devastates the immune system because its main target is the T4 lymphocyte, which is the key component for generating and regulating the immune response. The cellular receptor for HIV, the membrane glycoprotein CD4, is found mainly on the surface of this major subpopulation of T lymphocytes and also on many other cell types such as those of the monocyte/macrophage series. HIV can destroy CD4 cells by direct virus cytotoxicity and indirectly through the host response against HIV-infected cells or gp120-targeted cells. Cells of the macrophage lineage are generally not destroyed but serve as a reservoir of virus. HIV also causes functional impairment in T cells, B cells and monocytes. The virus can exist in latent or chronic form. The mechanisms of cellular destruction, viral persistence and conversion to a productive infection are being studied vigorously. Host factors that may affect clinical outcome and immunological markers that may predict progression of HIV disease are presently delineated. Prolonged serological latency may follow infection with HIV. Protective humoral and cell-mediated immune responses to HIV are either poor or not sustained. Recent results on HIV-specific cytotoxic T lymphocytes are of great interest. These cytotoxic cells, particularly those directed to gp120 targets, probably contribute to cellular damage. A central question regarding immunity to HIV is its beneficial versus deleterious effects, particularly in regard to the eventual development of an AIDS vaccine.

About 5-10% of HIV seropositive individuals, in all risk groups, develop a syndrome of immunological thrombocytopenic purpura (ITP). Despite the clear association between HIV infection and thrombocytopenia, the exact immune mechanism leading to the peripheral platelet destruction remains unclear. Whereas some data support the direct effect of autoantibodies to platelet constituents, other findings argue in favour of the deposition of immune complexes containing anti-HIV antibodies. Although viral components could not be detected in the immune complexes or on the platelet membrane, megakaryocytes were shown to contain viral RNA and there is some evidence for a direct or indirect role of HIV in the pathophysiology of this disorder. Steroids, intravenous high dose polyvalent immunoglobulin, anti-rhesus immunoglobulin, danazol and vincristine usually induce only a transient increase in platelet counts. Zidovudine was shown to provide a sustained response in 40-60% of the patients and appears to be the treatment of choice for HIV-related thrombocytopenia. Splenectomy has been effective in many cases with persistent, profound and symptomatic thrombocytopenia and, on a 4-year follow-up, does not influence the progression rate to AIDS or survival. Patients with thrombocytopenia are not at greater risk for the development of AIDS than seropositive non-thrombocytopenic patients. Thus, thrombocytopenia should not be viewed as a stage in the progression from asymptomatic infection to AIDS.

alpha-H chain diseases (HCD) is a human lymphoproliferative disorder, characterized by the production of truncated alpha-Ig H chains, without associated L chains. In this study, we have analysed the serum protein, the alpha-HCD mRNA and the rearranged alpha-HCD gene from the leukemic cells of a patient (MAL) with alpha-HCD. The abnormal MAL serum Ig consisted of short alpha 1-chains, lacking VH and CH1 domains (only CH2 and CH3 domains were present). The alpha-HCD mRNA (1.2 kb) was shorter than a normal alpha-mRNA (2 kb); the corresponding cDNA had sequences for the leader, a 84-bp sequence of unknown origin and the CH2 and CH3 exons. The establishment of the sequence of the productive alpha-HCD MAL allele revealed two major deletions; that of the VH region as well as that of the CH1 region. The JH region is altered by multiple mutations, small insertions and a duplication of the psi JH3 region. A large insert (INS1), of 360 bp (containing the 84 bp exon found in the cDNA), replaces the deleted VH region. INS1 is non-Ig related and apparently of nongenomic origin. A large second insert (509 bp), is located between the enhancer and the switch region. Insert2 contains repetitive non-Ig-related sequences and a small Ig-related sequence. All these alterations resulted in an abnormal mRNA, which comprises the leader, a 84-bp alien exon derived from INS1 and the CH2 and CH3 exons of the alpha 1-gene.

1. Two registries are to be established in association with WHO, with the object of gathering and recording information on cases of immunodeficiency from all over the world. One registry will comprise cases of primary immunodeficiency that have received transplants of any immunologically competent organ, cell, or cell product, e.g., bone marrow, thymus, or transfer factor. It will be organized by W. Hitzig and M. Seligmann. The other will comprise cases of malignant tumour found in patients with primary immunodeficiency; it will be organized by R. A. Good, who will also arrange for pathological material to be submitted for study by selected pathologists. The organizers will collate and periodically report on the material in both registries. 2. Standardization of diagnostic procedures and additional studies related to diagnostic tests are required. a. There is a need for standard preparations of antigens for assessing antibody formation as described. A sufficiently large batch of such antigens should be prepared, and aliquots should be sent, on request, for use by clinicians investigating immunodeficiency. b. Methods for measuring serum antibodies need to be standardized, and in vitro tests for the measurement of cell-mediated immunity, such as tests for cytotoxicity and macrophage migration inhibition factors, need to be further developed. 3. Therapeutic procedures should be standardized and assessed. a. Aggregates in immunoglobulin preparations for intramuscular or intravenous injection should be looked for with tests such as those recommended. b. National agencies responsible for immunoglobulin production should develop stable aggregate-free intact IgG, without fragments and with relatively normal in vivo survival, for the treatment of patients with immunodeficiency. c. It would be of value to determine the relative effectiveness of therapy with immunoglobulin and with plasma. Clinical trials might be designed for this purpose. d. Immunoglobulin preparations having high contents of specific antibodies would, if available, be valuable for treatment of patients with specific infections. e. Further research is required to develop new methods of destroying the biological activity of lymphocytes in whole blood. f. Pools of immunoglobulin, prepared as Cohn FII from donors with absence of One genetic allotype, may be valuable for the treatment of patients with immunodeficiency who have anti-allotype antibodies.

Fourteen cases of transient serum monoclonal immunoglobulins are reported. Seven of the patients were young children. In 8 cases (including 5 children) a primary or secondary immunodeficiency could be ascertained. The level of the peak was under 1 g % in all cases except one, where the monoclonal Ig level was 2.5 g %. In 9 cases the monoclonal Ig disappeared in less than 2 months. The significance of these transient homogeneous components is discussed at both the clinical and aetiological level.

The pepsin digestion of two Waldenstrom IgM globulins at pH 4·5 resulted in their total conversion into small peptides after 48 hr. During the proteolysis process, two main split products were isolated. They were physicochemically and immunologically characterized and designated as Fab′μ and F(ab″)2μ fragments. The maximum yield of the Fab′μ fragment was 20 per cent at 24 hours' digestion. This 3·8S fragment has a slow electrophoretic mobility and is similar to but not identical with the corresponding papain Fabμ fragment. It consists of one light chain and one Fd′ piece, both of which were isolated. The F(ab″)2μ fragment, which wa isolated under limited conditions of proteolysis, is a disulfide linked dimer. Its monomer Fab″ is larger that the Fab′ fragment since it contains a μ chain segment which extends more towards the C-terminal than the Fd′ piece. The F(ab″)2μ fragment is rapidly converted to Fab′ fragments during peptic proteolysis. The comparative study of the pepsin and papain digestion fragments allows the delineation of several segments on the μ-polypeptide chains. The extensive proteolysis of IgM globulins by pepsin is presumably due to their higher tendency than IgG globulins to polypeptide chain unfolding at pH 405.

Neoplastic cells from 9 patients affected with a "histiocytic" lymphoma were studied with 5 membrane markers of B or T lymphocytes. In 2 patients a monoclonal B-cell proliferation was found; they had been affected previously with well documented B-cell proliferations: chronic lymphocytic leukemia or Waldenstrom's macroglobulinemia. The blast cells of 2 other patients had T-cell features; in a fifth case, the abnormal cells carried only a strong receptor for the Fc fragment of IgG, which suggested their truly monocytic origin. In 4 patients, the cells had no detectable surface markers. These findings demonstrated that this group of lymphomas is heterogenous, that the term "histiocytic" appears to be wrong in most instances, and that the cellular origin of the malignant cells frequently remains unidentified and thus prevents a satisfactory new classification.

Monoclonal B lymphocyte populations from the bone marrow of seven cases of Waldenstrom's macroglobulinemia were studied for membrane IgD and IgM. In all cases lymphocytes with both classes on the membrane were found as well as cells with IgD or IgM only; the relative percentages of these three groups of lymphocytes were different in different cases. The IgM-containing plasma cells always had membrane IgM and some of these also had IgD. Of particular interest was one patient whose macroglobulin had an anti-IgG reactivity. The peripheral blood B lymphocytes of this patient had both membrane IgM and membrane IgD: it was possible to show, by capping with anti-IgG or with aggregated IgG, that both classes of immunoglobulin receptors shared reactivity with human IgG.

The pathological and clinical features of alpha-chain disease, its immunological diagnosis, the structural abnormalities of the abnormal immunoglobulin A compared with those of proteins of gamma and mu heavy chains diseases, the course of the disease and its present treatment, the epidemiological factors involved and their influence on pathogenesis and finally, the relationship with the "Mediterranean abdominal lymphoma" or IPSID are successively described. The stress has been placed on the latest data which refine but no not modify the first description of the disease. In the same way as studies on the synthesis and structure of proteins in heavy chain diseases will provide new data on the biosynthesis of normal immunoglobulins, so the elucidation of sequential events leading from a plasmocytic stage reversible by antibiotic therapy alone to a highly malignant immunoblastic stage should improve our knowledge of the genesis of human lymphomas.

A case of systemic lupus erythematosus associated with an homozygous deficiency in the second fraction of complement is reported and compared to previous reports of the literature. The high incidence of infections in these patients is outlined. The defective gene in this family was associated with the HLA A10B18 haplotype and the propositus was homozygous at the HLA-D locus. Familial study allowed the detection of 3 heterozygous individuals two of them being symptomatic (vascular purpura, high incidence of bacterial infections).

An increased frequency of HLA-DR5 antigen is reported in 34 patients with thrombocytopenic purpura HIV related. That increase of HLA-DR5 antigen support the fact that DR5 could be the witness of the predisposition to develop clinical symptoms.

The authors report the chance discovery in a man aged 53 years with serum positive rheumatoid arthritis, of gamma 3 heavy chain disease. The originality of this case depended on the absence of any detectable lymphoid proliferation and on the transient character of the pathological protein. Only the course after a long follow up will determine whether there is no incipient lymphoid proliferation and whether the heavy chain disease has disappeared permanently.

Surface IgD on blood lymphocytes was studied in 10 normal adults and 24 patients with primary immunodeficiencies by direct immunofluorescence, together with surface immunoglobulins of the other classes and with spontaneous rosette formation with sheep erythrocytes. In the normal adults, 8% of the lymphocytes bore delta chains (the figures for mu chains being 11%) and, among the cells positive for mu and/or delta, 70% were mixed stained, 22% and 8% being single stained for mu and delta respectively. In 10 patients with sex-linked agammaglobulinemia or variable immuno-deficiency, practically no cells bearing surface immunoglobulins, including IgD, were detectable. A normal distribution of surface immunoglobulins, including the results of double labeling for mu and delta, was found in five other immunodeficiency patients in whom there was a block of the terminal differentiation of B lymphocytes into plasma cells. A new kind of block in the differentiation of the B cell line was observed in two patients affected with sex-linked severe combined immunodeficiency and variable immuno-deficiency respectively. They showed high figures for IgD-bearing lymphocytes, some of which carried simultaneously mu chains, contrasting with the absence of lymphocytes carrying IgM without IgD and of IgG- or IgA-bearing cells. The data obtained in several other patients with low figures for IgG- and IgA-bearing lymphocytes and a predominance of IgD-carrying cells with an excess of single producers for delta chains over single producers for mu chains suggest an analogous but incomplete maturation arrest.

Richter's syndrome (RS) has been defined as "histiocytic" lymphoma (HL) or Hodgkin's disease (HD) supervening in the course of chronic lymphocytic leukemia (CLL) and related disorders. The clinical, histologic, and immunologic findings in 25 cases (11 women, 14 men) of RS are presented. The initial diagnosis was CLL in 19 cases, diffuse well-differentiated lymphocytic lymphoma in 2 cases, and Waldenstrom's macroglobulinemia in 4 cases. The interval between the initial diagnosis and that of RS ranged from 0 (two cases) to 120 months (median 49 months). At the time of diagnosis of RS, the initial lymphoproliferative disorder was in apparent complete remission in only two cases. The lymphoma was disseminated in at least 18 cases. The overall median survival was four months, but complete remission was achieved in six cases and has been maintained for 15 to 77 months. In four of these six cases, the RS was localized. The histologic diagnosis of HD was made in only two cases. In the other 23 cases, the diagnosis was HL, but in five of these cases, the proliferation was heterogeneous and was considered as an early aspect of HL. Immunologic studies of lymph node cell suspensions were performed in seven cases. In all cases, the B-lymphocytic origin of the lymphoma cells could be ascertained. Detailed studies in four cases showed that lymphoma cells carried SIg of the same isotype and light chain type as that of SIg detected on CLL cells or of monoclonal serum Ig. In these cases, the lymphoma was actually related to the initial B-cell chronic lymphoid disease.

The study of membrane markers of the proliferating cells in peripheral T cell neoplasia, in acute lymphoblastic leukemias and in various B-derived malignancies has allowed to get insight into the various steps of the differentiation process of normal human lymphoid cells.

We describe herein the occurrence of a T cell-derived blast crisis of chronic myelocytic leukemia which presented as a typical T cell leukemia on clinical (thymic mass and high white blood cells) and immunological grounds (T6+ T4+ T8+), with rearranged T cell receptor genes and germ line immunoglobulin genes. A Philadelphia chromosome was detected in all blast cell mitoses. The significance of T cell involvement during the chronic and acute phases of chronic myelocytic leukemia is discussed.