Emergence of activated lymphocytes in CD4 and CD8 subpopulations of multiple myeloma: correlation with the expansion of suppressor T-cells (CD8+ OKM1+) and ecto-5'nucleotidase deficiency

This study of CD4 and CD8 lymphocyte subpopulations in MM revealed increased proportions of cells expressing OKM1, Leu7, and HLA-DR antigens. In CD8 lymphocytes, there was a direct correlation between OKM1 and HLA-DR positivity. Two-colour analysis of purified CD8 subpopulations showed that HLA-DR was preferentially expressed by OKM1+ lymphocytes (suppressor cells), but a significant proportion of OKM1-lymphocytes (cytotoxic precursor cells) were also HLA-DR+. A significant proliferative activity found in CD2 lymphocytes was directly correlated with the proportion of HLA-DR+ cells in CD8 subpopulations only. CD8 lymphocytes displayed significantly lower 5'NT activity than those of normal subjects. This enzyme deficiency was correlated with the expansion of CD8 OKM1+ and HLA-DR+ cells; the increase in suppressor cells, as well as the emergence of activated cells, are associated with CD8 5'NT deficiency. In conclusion, the immunological pattern of CD4 and CD8 subpopulations in MM is significantly different from that in normal subjects. The implications of these data for the immune dysregulation occurring in MM are discussed.     

Both early and committed haemopoietic progenitors are more frequent in peripheral blood than in bone marrow during mobilization induced by high-dose chemotherapy + G-CSF

Summary. Haemopoietic growth factor administration following high-dose chemotherapy markedly amplifies progenitor cell pool in the peripheral blood (PB). Collection and reinfusion of these cells enable rapid haemopoietic recon-stitution following autograft. Less is known on engraftment potentiality of bone marrow (BM) cells taken under analogous conditions. To investigate this tissue, PB and BM were evaluated simultaneously during maximal mobilization in a series of 14 patients undergoing the HDS chemotherapy programme. A significantly higher growth of committed progenitors was found from PB rather than from BM (663 ± 123 v 267±40CFU-GM/10⁵ MNC, respectively). Also, significantly more CFU-GM could be collected by a median of three leukaphereses, compared to those harvested from BM (158 ± 31 v 16 ± 4 ± 10⁴ CFU-GM/kg, respectively). Most mobilized CFU-GM were phenotypically immature (CD15⁻); in addition, circulating cells included primitive progenitors, as assessed by LTC-IC assay, or by evaluation of non-proliferating pre-CFU-GM, selected by an anti-CD71 immunotoxin. The amount of pre-CFU-GM determined by both techniques was consistently higher in PB than in BM. Moreover, a direct correlation could be established between circulating CFU-GM and primitive precursors. Thus, during optimally induced mobilization, PB contains many more haemopoietic progenitors, of both committed and primitive stages, than does BM. Under such conditions, PB is probably the best source of material for graft purposes.     

Rapid generation of antiplasma cell activity in the bone marrow of myeloma patients by CD3-activated T cells

We have recently shown that peripheral blood T cells of multiple myeloma (MM) patients are very susceptible to stimulation of the T-cell receptor/CD3 complex with anti-CD3 monoclonal antibodies (MoAbs). CD3 stimulation is currently under clinical investigation as a nonspecific approach to boost antitumor effector mechanisms. The aim of this study was to determine whether the hyperreactivity of MM T cells to CD3 stimulation could be exploited to generate antitumor activity. Bone marrow mononuclear cells (BMMCs) from 65 MM patients were stimulated with the anti-CD3 MoAb OKT3 and the effect of this stimulation on autologous T cells and plasma cells was evaluated. The number of CD3+ CD25+ cells on day 6 was significantly higher in MM than the controls (30 normal individuals) (P = .001). Kinetic studies showed that 3H- thymidine incorporation peaked on day 3 and that the T-cell expansion peaked on days 5 and 6. In MM, T-cell activation markedly affected the survival of autologous plasma cells; their number in OKT3-treated cultures was significantly lower than in unstimulated cultures (P < .0001). T-cell activation and plasma cell decrease were not observed when T cells were removed from BMMC preparations. MM produced significantly higher levels of interferon-gamma (P = .005) and tumor necrosis factor-beta (P = .001), but lower levels of tumor necrosis factor-alpha (P < .001) than normal individuals. Interferon-gamma only was partially involved in CD3-induced plasma cell killing. Transwell cultures showed that the main mechanism by which CD3+ CD25+ cells affected plasma cells was direct cell-to-cell contact rather than cytokines. In conclusion, T cells in MM BMMCs possess distinct features in terms of susceptibility to CD3 stimulation and cytokine production compared with normal bone marrow T cells that can be exploited to generate antiplasma cell activity.     

Immediate and medium-term outcomes following the treatment of very long (> or =50 mm) chronic total coronary artery occlusions

OBJECTIVE: The follow-up patency rates and associated clinical and angiographic variables following stenting of very long (> or =50 mm) and chronic (>6 months) total coronary artery occlusive lesions are not well documented. The aim of the present study was to evaluate the early results and mid-term outcomes following angioplasty of such lesions. METHODS: Between January 2000 and June 2002, we treated 278 chronic coronary occlusions. Of these, eighty-nine occlusions (89 patients) were with lesions > or =50 mm long; these patients constituted the study population. RESULTS: Mean duration of occlusion was 7 +/- 2 months (range, 6-13 months). Procedural success was obtained in 81 patients. A total of 211 coronary stents (2.6 +/- 1.1 stents/patient) were implanted, and mean stent length was 59 +/- 9 mm. In 3 patients, TIMI flow 1-2 was observed after stent implantation. Thus, the angiographic success was considered to be 78/89 patients (87.6%). Periprocedural major adverse cardiac events occurred in 6 patients (6.7%). Clinical success was obtained in 74 patients (83%). During a 9.6 +/- 2 month follow-up, forty-three patients (55.1%) remained angina free, thirty-two (41%) had recurrence of angina, three patients (3.9%) had a new myocardial infarction and no deaths were reported. Target vessel revascularization was required in 34 patients (43.6%). Angiographic follow-up was obtained in 70 patients (90%) at a mean of 7.4 +/- 2 months. Restenosis was observed in 36 patients (51%), six of whom had reocclusion. A significant correlation was observed between the need for reintervention and stent length (R 0.52), residual stenosis (R 0.73) and diabetes mellitus (0.68). CONCLUSION: Although coronary artery stenting for very long (> or =50 mm) chronically occlusive lesions is feasible, safe and associated with a low incidence of periprocedural adverse clinical events, these complex and expensive procedures still have a high 6-month restenosis rate. These results might be significantly improved with the advent of drug-eluting stents.