A model for the origin of TCR-alphabeta+ CD4-CD8- B220+ cells based on high affinity TCR signals.

The origin of TCR-alphabeta+ CD4-CD8- cells is unclear, yet accumulating evidence suggests that they do not represent merely a default pathway of unselected thymocytes. Rather, they arise by active selection as evidenced by their absence in mice lacking expression of class I MHC. TCR-alphabeta+ CD4-CD8- cells also preferentially accumulate in mice lacking expression of Fas/APO-1/CD95 (lpr) or Fas-ligand (gld), suggesting that this subset might represent a subpopulation destined for apoptosis in normal mice. Findings from mice bearing a self-reactive TCR transgene support this view. In the current study we observe that in normal mice, TCR-alphabeta+ CD4-CD8- thymocytes contain a high proportion of cells undergoing apoptosis. The apoptotic subpopulation is further identified by its expression of B220 and IL2Rbeta and the absence of surface CD2. The CD4-CD8- B220+ phenotype is also enriched in T cells that recognize endogenous retroviral superantigens, and can be induced in TCR transgenic mice using peptide/MHC complexes that bear high affinity, but not low affinity, for TCR. A model is presented whereby the TCR-alphabeta+ CD2- CD4-CD8- B220+ phenotype arises from high intensity TCR signals. This model is broadly applicable to developing thymocytes as well as mature peripheral T cells and may represent the phenotype of self-reactive T cells that are increased in certain autoimmune conditions.

Liver damage preferentially results from CD8(+) T cells triggered by high affinity peptide antigens.

Little is understood of the anatomical fate of activated T lymphocytes and the consequences they have on the tissues into which they migrate. Previous work has suggested that damaged lymphocytes migrate to the liver. This study compares class I versus class II major histocompatibility complex (MHC)-restricted ovalbumin-specific T cell antigen receptor (TCR) transgenic mice to demonstrate that after in vivo activation with antigen the emergence of CD4(-)CD8(-)B220(+) T cells occurs more frequently from a CD8(+) precursor than from CD4(+) T cells. Furthermore, this change in phenotype is conferred only by the high affinity native peptide antigen and not by lower affinity peptide variants. After activation of CD8(+) cells with only the high affinity peptide, there is also a dramatically increased number of liver lymphocytes with accompanying extensive hepatocyte damage and elevation of serum aspartate transaminase. This was not observed in mice bearing a class II MHC-restricted TCR. The findings show that CD4(-)CD8(-)B220(+) T cells preferentially derive from a CD8(+) precursor after a high intensity TCR signal. After activation, T cells can migrate to the liver and induce hepatocyte damage, and thereby serve as a model of autoimmune hepatitis.

Outpatient supportive therapy after induction to remission therapy in adult acute myelogenous leukaemia (AML) is feasible: a multicentre study.

Twenty-four adult patients with AML were treated with standard "7 + 3" chemotherapy. After administering the myeloablative drugs in the hospital, patients were instructed to continue their supportive treatment on an outpatient basis; they received ciprofloxacin, cotrimoxasole and itraconazole vo until the absolute granulocyte count rose above 1 x 10(9)/l. Platelet concentrates were given every other day until the platelet count rose above 20 x 10(9)/l. Complete remission (CR) was obtained in 87%. Fever developed in 29% and 2 cases were complicated by indwelling-catheter-related Pseudomona aeruginosa septicaemia, 1 Entamoeba hystolytica enteritis and 1 Pneumocystis carinii pneumonia; these patients were hospitalized to treat these infections specifically. In no case was the infection fatal. The median disease free-survival (DFS) was 17 months, 12-month DFS was 66%, and 30-month DFS was 17%. Our calculations have shown that 1700 USD/patient were saved by avoiding prolonged hospitalization; this may provide not only economical, but also psychological advantages to patients.

[Response of insulin and C-peptide to a mixed meal in non-insulin-dependent diabetics treated with insulin and chlorpropamide]. / Respuesta de insulina y péptido C a una comida mixta en diabéticos no insulinodependientes tratados con insulina y cloropropamida.

Glucose control in NIDDM is prone to progressive deterioration due to secondary failure to oral hypoglycemic therapy. Insulin may subsequently be required for optimal control in spite of peripheral hyperinsulinemia. In Mexico, diabetes associated with obesity is common. We therefore designed a prospective study combining insulin and chloropropamide in order to evaluate any improvement in insulin response to a standardized meal load and a consequent amelioration of glucose control. METHODS. Twenty diabetic patients with secondary failure to full doses of hypoglycemic drugs and moderate hyperglycemia were recruited. Therapy was initiated with human insulin 20 IU/day and 500 mg cholopropamide, titrating insulin dosage in order to achieve euglycemia. Before treatment and at the end of the study period, a glucose/insulin/C peptide response curve to a mixed standardized meal was performed. Blood glucose, serum lipids fructosamine and glycosylated hemoglobin levels were also determined. All patients were followed by capillary glucose measurements three times a week and glucose and fructosamine concentrations every two weeks during the study period. RESULTS. All patients required less insulin, and glucose control improved significantly. Glucose, fructosamine and glycosylated hemoglobin levels decreased from 262 mg/dL, 369 mmol/L and 14% to 111 mg/dL, 252 mmol/L, and 8% respectively; all differences were statistically significant. Insulin and C peptide levels increased significantly from 22.2 mU/mL and 1.65 ng/mL to 29.8 mU/mL and 1.97 ng/mL, respectively. When we measured the area under the curve, total values improved from 110 and 7.69 to 127 and 9.37, respectively; this was also statistically significant. Lipids levels decreased significantly, including triglicerides, total and LDL cholesterol whereas HDL cholesterol levels increased. CONCLUSIONS. Glucose control improved in our patient cohort the pancreatic insulin response probably due to a more adequate glycemic microenvironment and a possible enhanced exogenous and endogenous insulin function.

Survival of patients with advanced HIV infection treated with 300 mg/d of zidovudine: a prospective study.

In this prospective study we analyze the long-term survival using 300 mg/day zidovudine (AZT) in patients with advanced forms of human immunodeficiency virus infection. The study is in a private-practice setting, over a 5-year period, and includes 72 patients with advanced human immunodeficiency virus infection (categories C1, 2 or 3). The median survival (SV) is above 60 months (24-months SV 65% and 60-month SV 54%). According to the number of CD4 cells at diagnosis it was found that patients with above or below 200 CD4 T cells had a median SV of above 60 and 18 months (p < 0.001) and a 24-month SV 88 and 45% (p < 0.001); for patients with CD4 cells below 20 at diagnosis, the median survival was even lower (three months) and the 12-month survival less than 18%. It is concluded that the results of treating HIV-infected patients with AZT 300 mg/day are similar to those reported by others using higher doses of AZT. A low dosage is also more easily available to a larger number of HIV-infected individuals.

Interleukin-1 and interleukin-6 activities are increased in the cerebrospinal fluid of patients with CNS lupus erythematosus and correlate with local late T-cell activation markers.

We examined cerebrospinal fluid (CSF) samples from 12 patients with SLE and active central nervous system (CNS) involvement for their levels of the following cytokines: interleukin-1 (IL-1) by means of two different assays--the IL-1 responsive murine cell line LBRM 33-la5 and an ELISA for IL-1 alpha; IL-2 by means of the CTLL cell line responsive to it; and interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) both determined by a specific ELISA. We found that SLE CSF had significantly higher levels of IL-1 and IL-6 than did those obtained at surgery from eight controls without inflammatory neurologic disease. IL-2 and TNF were not detectable in any of the CSF samples. We also studied the status of activation in CSF T cells using monoclonal antibodies against early (anti-IL-2R (CD25) and anti-transferrin (CD71)), late (anti-T10) and very late (anti-VLA-1) activation antigens, and found increased percentages of T10-bearing (18 +/- 2 vs 3 +/- 0.7%) and VLA-1-bearing T cells (12 +/- 2 vs 0.7 +/- 0.2%) in SLE patients as compared to controls (both P < 0.01). Levels of IL-1 and IL-6 correlated with T10 and those of IL-1 correlated also with VLA-1. Markers of early T-cell activation did not differ in SLE and control CSF. Because of these findings we analysed the effect of recombinant IL-1, IL-6 or normal CSF on normal T cells and found that they did not induce the expression of activation markers.(ABSTRACT TRUNCATED AT 250 WORDS)