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S Sica

Publications and source records attributed to S Sica.

At least 37 records · Page 2Linked to original sources
PubMed2001

Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions.

OBJECTIVE: The aim of this study was to evaluate the occurrence of T-cell spontaneous apoptosis (A(spont)) and its modulation in vitro by the interleukin-2 receptor (IL-2R) gamma-chain (gammac)-signaling cytokine IL-15 in patients transplanted with autologous peripheral blood progenitor cells (PBPC) for hematologic malignancies. MATERIALS AND METHODS: Patients were examined on days 30-60, 60-90, and 90-120 after PBPC infusion. Dissipation of mitochondrial transmembrane potential, a hallmark of T-cell apoptosis, has been detected using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide, after short-term T-cell culture in the absence or presence of exogenous cytokines. Expression of Bcl-2 family members has been studied by flow cytometry and reverse transcriptase polymerase chain reaction. T-cell proliferative responses to recall antigens have been estimated in autologous mixed leukocyte cultures. RESULTS: A(spont) was seen in 45% +/- 6% of CD4(+) and 55% +/- 6% of CD8(+) T cells cultured in the absence of cytokines. Of interest, IL-15 and, to a lesser extent, its structural cousin IL-2 counteracted T-cell A(spont) by inhibiting the processing of caspase-3 and up-regulating Bcl-2 mRNA and protein levels. Cell division tracking confirmed that IL-15 did not rescue T cells from A(spont) by promoting proliferation but rather acted as a genuine survival factor. Addition of a gammac-blocking antibody to cytokine-conditioned cultures abrogated both apoptosis inhibition and Bcl-2 induction by IL-15, suggesting involvement of the IL-2Rgammac signal transduction pathway. Whereas cytokine-unprimed posttransplant T cells mounted inadequate responses to recall antigens, T cells conditioned with IL-15 expanded vigorously, indicating restoration of antigen-specific proliferation. CONCLUSIONS: T cells recovering after autologous PBPC transplantation are highly susceptible to spontaneous apoptosis in vitro. This phenomenon can be counteracted by the gammac-signaling cytokine IL-15. These findings suggest that IL-15 might be a promising immunomodulating agent to improve postgrafting T-cell function.

Actins↗
PubMed2001

Immune reconstitution after autologous selected peripheral blood progenitor cell transplantation: comparison of two CD34+ cell-selection systems.

BACKGROUND: Selection of CD34+ PBPCs has been applied as a method of reducing graft contamination from neoplastic cells. This procedure seems to delay lymphocyte recovery, while myeloid engraftment is no different from that with unselected PBPC transplants. STUDY DESIGN AND METHODS: Lymphocyte recovery was studied in two groups of patients who underwent autologous CD34+ PBPC transplant with two different technologies (Ceprate SC, Cellpro [n = 17]; CliniMACS, Miltenyi Biotech [n = 13]). The median number of CD34+ cells transfused was 3.88 x 10(6) per kg and 3.32 x 10(6) per kg, respectively. Residual CD3 cells x 10(6) per kg were 4.97 and 0.58, respectively (p = 0.041). Residual CD19 cells x 10(6) per kg were 1.33 and 0.73, respectively (NS). RESULTS: No differences were found between the two groups in total lymphocyte recovery to >0.5 x 10(9) per L, which achieved a stable count by Day 30. During the study period, the CD4+ cell count remained below 0.2 x 10(9) per L, and the B-cell subset showed a trend toward normalization. CD3/HLA-DR+ and CD16/56 increased markedly in both groups by Day 30. An increase in CMV (13%) and adenovirus (17.4%) infection was found in both groups. CONCLUSION: Both CD34+ cell selection technologies used here determined an excellent CD34+ cell purity and an optimal depletion of T cells. The high rate of viral complications is probably due to the inability of residual T cells left from the CD34+ cell selection to generate, immediately after transplant, an adequate number of virus-specific lymphocytes.

Adolescent↗
PubMed2001

Immune reconstitution following transplantation of autologous peripheral CD34+ cells.

The recovery of lymphocyte count, CD4+ and CD8+ T-cell subsets, natural killer (NK) cells and CD19+ B cells has been evaluated during the first 4 months after the infusion of autologous CD34+ peripheral blood progenitor cells (PBPC; group A; 33 patients) or autologous unselected PBPC (group B; 36 patients) for hematological malignancies. Lymphocyte count promptly recovered in both patient cohorts, although the repopulation of CD3+ T cells occurred more rapidly in group B compared with group A. The count of CD4+ T lymphocytes remained <200/microl during the study period in patients transplanted with CD34+ PBPC, being significantly lower compared with group B (p = 0.0019 and p = 0.0035 on days 30 and 60, respectively). CD8+ T cells rapidly increased both in group A and B and CD4 to CD8 ratio was severely reduced. CD4+ and CD8+ T cells displayed an activated phenotype in both groups of patients, coexpressing the HLA-DR antigen throughout the study period. No differences in the repopulation kinetics of NK cells and CD19+ B cells were observed. Further investigations are encouraged to characterize T cell competence following transplantation of CD34+ PBPC.

Adolescent↗
PubMed2001

Therapy related leukemias: susceptibility, prevention and treatment.

Acute leukemia is the most frequent therapy-related malignancy. Together with the increasing use of chemo- and radiotherapy, individual predisposing factors play a key role. Most of secondary leukemias can be divided in two well-defined groups: those secondary to the use of alkylating agents and those associated to topoisomerase inhibitors. Leukemias induced by alkylating agents usually follow a long period of latency from the primary tumour and present as myelodysplasia with unbalanced chromosomal aberrations. These frequently include deletions of chromosome 13 and loss of the entire or of part of chomosomes 5 or 7. The loss of the coding regions for tumor suppressor genes from hematopoietic progenitor cells is a particularly unfavourable event, since the remaining allele becomes susceptible to inactivating mutations leading to the leukemic transformation. The tumorigenic action of topoisomerase inhibitors is on the other hand due to the formation of multiple DNA strand breaks, resolved by chromosomal translocations. Among these, chromosome 11, band q23, where the myeloid-lymphoid leukemia (MLL) gene is located, is often involved. Frequent partners are chromosomes 9, 19 and 4 in the t(9;11), t(19;11) and t(4;11) translocations. Younger age, a mean period of latency of 2 years and monocytic subtypes are characteristic features of this type of leukemia. Among patients at risk for secondary leukemia, those with Hodgkin's disease are the most extensively studied, with the major impact of alkylating agents included in the chemotherapy schedule. The same is true for non-Hodgkin's lymphoma, while in multiple myeloma and acute lymphoblastic leukemia determinants are the dose of melphalan and of epypodophyllotoxin, respectively. Patients with breast, ovarian and testicular neoplasms are also at risk, in particular if trated with the association of alkylating agents and topoisomerase II inhibitors. According to the EBMT registry, in patients with lymphoma treated with high-dose therapy and autologous stem cell transplantation the cumulative risk of inducing leukemia at 5 years is 2.6%. Among treatment options, supportive therapy is indicated in older patients, while allogeneic stem cell transplantation, related or matched-unrelated, is feasible in younger patients. These data indicate the need for the identification of predisposing factors for secondary leukemia. In particular, frequent follow-up of patients at high-risk should be performed and any peripheral blood cytopenia should be considered suspicious. Whenever possible, the exclusion of drugs known to be leukemogenic from the treatment schedules should be considered, especially in young patients.

Acute Disease↗
PubMed2001

Blood cells diseases and thrombosis.

BACKGROUND AND OBJECTIVES: In recent years knowledge about thrombophilia and the mechanisms underlying the pathogenesis of thrombosis has increased greatly. Nevertheless the role of leukocytes and red cells in thrombogenesis is not well established and is probably underestimated. EVIDENCE AND INFORMATION SOURCES: The contribution of leukocytes and red cells to thrombogenesis has been reviewed. Moreover, the prevalence of thrombosis as a complication of hematologic diseases has been examined. The authors are involved in the investigation and management of acute and chronic hematologic diseases as well as in investigation of thrombophilia. Pub-Med was employed as a source of information. STATE OF THE ART: Thrombosis is a major problem in myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. A clonal involvement of megakaryocytopoiesis resulting in elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface is regarded as the main origin of thromboembolism; nevertheless, activation of leukocytes and the consequent release of elastase and alkaline phosphatase could play an important role, determining endothelial damage. Thrombosis is a relevant problem in some hemolytic anemias such as paroxysmal nocturnal hemoglobinuria and drepanocytosis. Thrombotic events in hemolytic anemias with membrane defects have been attributed, at least in part, to hypercoagulability related to the exposure of phosphatidylserine of red cell membrane activating plasma prothrombinase and supplying a procoagulant phospholipid anionic surface. A moderate but well-established risk for thrombosis occurs in acute promyelocytic leukemia and acute lymphoblastic leukemia; this risk could be increased by antiblastic drugs affecting the procoagulant activity of cells and the production of coagulation inhibitors from the liver. PERSPECTIVES: Thrombotic complications during hematologic diseases other than thrombophilia due to plasma alteration could be decreased not only by anticoagulant and antiaggregating agents but also by drugs inhibiting activation of leukocytes and red cells and their interaction with platelets.

Animals↗
PubMed2000

Granulocyte colony-stimulating factor perturbs lymphocyte mitochondrial function and inhibits cell cycle progression.

Sera from healthy subjects receiving recombinant human granulocyte colony-stimulating factor (rHuG-CSF) to mobilize CD34(+) peripheral blood progenitors (PBPC) have been recently shown to induce unresponsiveness of allogeneic lymphocytes to mitogenic challenge. In the present investigation, the effects of rHuG-CSF on the early stages of lymphocyte activation-induced apoptosis and on lymphocyte cell cycle entry were evaluated. Sera were obtained from HLA-identical donors receiving rHuG-CSF to mobilize CD34(+) PBPC for allogeneic transplantation. Normal peripheral blood mononuclear cells (PBMC) were challenged with phytohemagglutinin (PHA) in the presence of serum collected before (preG) or after rHuG-CSF administration (postG). Mitochondrial function, that is, incorporation of 3,3'-dihexyloxacarbocyanine iodide [DiOC(6)(3)] and generation of reactive oxygen species (ROS) as well as expression of c-Myc and Bcl-2 family members (Bcl-2, Bcl-X(L), Bax) were evaluated by multiparameter flow cytometry. The activation-induced fragmentation of genomic DNA was detected by highly sensitive LM-PCR assay.CD4(+)DiOC(6)(3)(low) and CD8(+)DiOC(6)(3)(low) T lymphocytes increased and reached 32% (range 27%-38%) and 20% (range 15%-23%) of circulating T cells, respectively, on day 4 of rHuG-CSF administration. Hypergeneration of ROS could be demonstrated in 65% (range 58%-82%) of CD4(+) T lymphocytes and in 0.4% (range 0.2%-0. 8%) of circulating CD8(+) T cells. rHuG-CSF determined no alteration of mitochondrial function if added to allogeneic PBMC in vitro, thus suggesting indirect effects mediated by soluble factors; on the contrary, when PBMC were challenged with PHA in the presence of postG serum, both perturbation of mitochondrial transmembrane potential (Deltapsi(m)) and hypergeneration of ROS were induced, and lymphocytes were predominantly arrested in a G(0) -like phase of the cell cycle and displayed genomic DNA fragmentation. Interestingly, the preincubation of PBMC with a blocking antibody directed against CD95 abrogated the perturbation of lymphocyte Deltapsi(m), suggesting that the CD95 signaling pathway might play a role in the induction of apoptosis after PHA stimulation in the presence of postG serum. Moreover, Bax protein was overexpressed in postG (median fluorescence intensity = 180, range 168-186) compared with preG cultures (median fluorescence intensity = 75, range 68-80; p < 0.01), while no differences in Bcl-2, Bcl-X(L), and c-Myc staining intensity were observed. Our findings demonstrate a humoral-mediated rHuG-CSF-induced dissipation of lymphocyte mitochondrial Deltapsi(m); these effects might be mediated by Bax overexpression, with imbalance between apoptosis-promoting and apoptosis-inhibiting Bcl-2 family members and with subsequent induction of mitochondrial permeability transition. Whether immune dysfunction will favorably impact on incidence and severity of acute graft vs host disease after allogeneic PBPC transplantation remains to be determined.

Adult↗
PubMed2000

MiCMA: an alternative treatment for refractory or recurrent Hodgkin's disease.

BACKGROUND: We determined the response rate to MiCMA (mitoxantrone, carboplatinum, methylprednisolone and aracytin) in a group of 29 patients with Hodgkin's disease (HD) and poor prognostic factors either resistant to first line or relapsing after conventional chemotherapy and subsequently evaluated the role of autologous stem-cell transplantation (ASCT) in these patients after MiCMA. PATIENTS AND METHODS: The treatment was intended as a brief tumor debulking program before ASCT. Twenty-nine patients with primary refractory HD or relapsed HD were submitted to two courses of MiCMA (mitoxantrone 10 mg/m2 day 1; carboplatinum 100 mg/m2 days 1-4; aracytin 2 g/m2 day 5; methylprednisolone 500 mg/m2 days 1-5) and subsequently evaluated for response. Those with responding or stable disease, received one or two other courses of MiCMA followed by ASCT. RESULTS: There were 10 complete responses (34% CR), 15 partial responses (52% PR) and 4 treatment failures with disease progression (14% PD). In total there were 25 evaluable responses out of 29 patients (86% CR + PR). Myelosuppression was the main toxicity of this treatment. At this time 20 patients (69%) are alive with a median follow-up of 26.5 months (7-100), 13 patients in CR (45%), 8 patients died, 7 of them from disease progression and one due to multi-organ failure, one patient is lost to follow-up. All but one of the patients who achieved CR after MiCMA are alive. Only the number of extranodal sites was found to predict a poor response to MiCMA. CONCLUSIONS: A short pre-transplantation treatment with MiCMA is an effective tumor debulking approach in patients with refractory or relapsed HD.

Adolescent↗
PubMed2000

Immune reconstitution after transplantation of autologous peripheral CD34+ cells: analysis of predictive factors and comparison with unselected progenitor transplants.

The recovery of lymphocyte count, CD4+ and CD8+ T-cell subsets, natural killer (NK) cells and CD19+ B-cells was evaluated in a cohort of 15 patients receiving autologous CD34+ peripheral blood progenitor cells (PBPCs; group A) for haematological malignancies and in 20 patients transplanted with autologous unselected PBPCs (group B). Lymphocyte count recovered in both patient cohorts, being significantly lower in group A than in group B 1 (P = 0.008) and 2 months (P = 0.0035) after progenitor cell infusion. The repopulation of CD3+ T-cells occurred more rapidly in group B than in group A (P = 0.034 on week 4); CD19+ B-lymphocytes did not return to reference ranges in either group of patients. The count of CD4+ T-lymphocytes remained < 200/microl during the study period in patients transplanted with CD34+ PBPCs, significantly lower than group B levels (P = 0.034 and P = 0.021 on weeks 4 and 8 respectively). CD8+ T-cells increased rapidly in both groups; thus, the CD4 to CD8 ratio was severely reduced. CD4+ and CD8+ T-cells displayed an activated phenotype in both groups of patients, co-expressing the HLA-DR antigen throughout the study period. NK cells followed a similar repopulation kinetics in both study groups, although their expansion was greater in group B than in group A (P = 0.014 on week 4). In the CD34+ group, post-transplant administration of granulocyte colony-stimulating factor predicted a faster lymphocyte recovery in multivariate analysis (P = 0.025); interestingly, the amount of passively transferred lymphocytes correlated inversely with time to achieve a lymphocyte count > 0.5 x 10(9)/l (r = -0.63, P = 0.01). Further investigations are necessary to characterize T-cell competence after transplantation of CD34+ PBPCs.

Adult↗
PubMed2000

Enhanced susceptibility to apoptosis in T cells recovering after autologous peripheral blood progenitor cell transplantation: reversal by interleukin-15.

T-cell number and competence are profoundly impaired after transplantation of autologous cytokine-mobilized peripheral blood progenitor cells (PBPC). The objective of the present study was to evaluate the occurrence of T-cell spontaneous apoptosis (Aspont) and its modulation in vitro by the interleukin-2 receptor (IL-2R) gamma-chain (gammac)-signaling cytokine interleukin-15 (IL-15) in the peripheral blood of patients transplanted with autologous PBPC for hematological malignancies. An average 45%+/-6% of CD4+ and 55%+/-6% of CD8+ T cells cultured in the absence of exogenous cytokines underwent Aspont; of interest, IL-15 and, to a lesser extent, its structural cousin IL-2 counteracted T-cell Aspont and upregulated Bcl-2 levels. IL-15 did not rescue T cells from Aspont by promoting proliferation, but rather it acted as a genuine survival factor. Furthermore, T-cell preincubation with a gammac-blocking antibody was capable of abrogating both apoptosis inhibition and Bcl-2 induction by IL-15. These in vitro findings suggest that IL-15 might represent a promising immunomodulating agent to improve T-cell function after autologous PBPC transplantation.

Adult↗
PubMed2000

Autologous graft-versus-host disease after CD34+-purified autologous peripheral blood progenitor cell transplantation.

Autologous graft-versus-host disease (GVHD) has been frequently reported after cyclosporine A (CsA) administration in the autologous setting. This complication is related to the disruption of self-tolerance mechanisms induced by CsA and may exert an antitumor effect. We report the spontaneous occurrence of autologous GVHD after CD34+-purified peripheral blood progenitor cell transplantation (PBPCT) in 5 out of 24 consecutive patients (20.8%). The syndrome was characterized by skin rash (5/5), pruritus (5/5), eosinophilia (5/5), and fever (2/5) occurring at a median of 37 days (range 22-60) after transplantation. Diagnosis was confirmed by skin biopsy in all patients. The syndrome was self-limiting, lasted a median of 25 days, and did not require treatment. The rate of autologous GVHD was high after CD34+-purified autologous PBPCT. In fact, no autologous GVHD was documented in an historical control of 100 consecutive patients submitted to unmanipulated PBPCT at the same institution. The manipulation of the graft by the purging procedure causes a profound T lymphocyte depletion, thus possibly perturbing the equilibrium between autoregulatory cells and autocytotoxic T cells. These observations add new interest to the antitumor efficacy of autologous GVHD and suggest new questions regarding the role of transplantation for autoimmune diseases.

Adolescent↗
PubMed2000

Autologous peripheral blood stem cell transplantation as first line treatment of multiple myeloma: an Italian Multicenter Study.

BACKGROUND AND OBJECTIVE: The outcome of patients with multiple myeloma (MM) has not changed markedly since the introduction of melphalan and prednisone. In recent years several studies have investigated the role of intensive therapy followed by infusion of autologous peripheral blood stem cells (PBSC) together with the administration of hematopoietic growth factors. In this study we evaluated the feasibility and efficacy of a PBSC transplantation program for patients with de novo MM in a multicenter setting. DESIGN AND METHODS: In a non-randomized controlled trial 52 patients with de novo MM from 6 Italian centers underwent a three phase treatment strategy including 3 cycles of VAD-like chemotherapy for initial debulking, followed by high-dose cyclophosphamide (HD-CY) and collection of PBSC, that were transplanted after a conditioning regimen with melphalan plus busulfan. Maintenance treatment was a conventional dose of interferon, given until relapse. Actuarial survival and response duration curves were plotted according to Kaplan and Meier's method; the groups were compared using the log rank test. Response rates were compared by the c(2) test; multivariate analysis was performed according to the stepwise regression model. RESULTS: Overall 39/52 (75%) of patients responded, with a complete remission (CR) rate of 31%. After a median follow-up of 55 months, median duration of event-free survival (EFS) and overall survival (OS) are 21 and 57 months, with 24% and 48% probabilities of being event-free and alive after 6 years, respectively. Among the group of 39 responders, CR was significantly associated with prolonged response and survival (2 deaths and 6 relapses/16 patients) as compared with PR (11 deaths and 15 relapses/23 patients), and remained the only significant variable also in a multivariate analysis. Myelosuppression did not protract beyond one week in transplanted patients; extra-hematologic toxicity was very low. INTERPRETATION AND CONCLUSIONS: This multicenter study confirms the feasibility of an aggressive approach to de novo MM patients. Additional confirmation is given of the increased rate of CR, and the significant prolonged survival observed in complete responders. In this experience the association melphalan plus busulfan was shown to be effective, at least as part of conditioning regimens, in the transplant strategy.

Adult↗