Showing papers by "Arnon Nagler published in 1997"

A fludarabine-based protocol for bone marrow transplantation in Fanconi's anemia

Abstract: Allogeneic bone marrow transplantation (BMT) is an effective therapy for Fanconi's anemia (FA) However, mortality and transplant-related complications are usually high due to increased sensitivity to the alkylating agents and radiation commonly used for pre-transplant conditioning Fludarabine monophosphate is a purine analogue that has been proven effective as a conditioning agent for chronic lymphocytic leukemia patients We report a child with FA in leukemic transformation with thrombocytopenia and 20% myeloblasts who underwent successful BMT following conditioning with fludarabine/ATG/cyclophosphamide The regimen was well tolerated, no transplant-related complications were observed, and engraftment was rapid The child is currently 10 months post-BMT, in excellent clinical condition with a normal blood count, 100% chimerism and no sign of graft-versus-host disease (GVHD) We suggest that this fludarabine-based regimen may be effective in the conditioning of standard, as well as transforming, FA patients for BMT

European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching

Abstract: We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 ± 3% at 2 years and leukemia-free survival (LFS) was 31 ± 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P = 0.001), acute GVHD

Interleukin-6 receptor-interleukin-6 fusion proteins with enhanced interleukin-6 type pleiotropic activities

Abstract: An sIL-6R/IL-6 chimera, directly fusing the natural forms of soluble IL-6 receptor and IL-6, as found in human body fluids, was produced in transfected human cells. The secreted p85 glycoprotein was active at a concentration of 120 pM to produce growth-arrest and spindleoid differentiation of murine melanoma F 10.9 cells, which do not respond to IL-6 alone. This fusion protein was as active as the yeast-produced p56 fusion protein containing a shortened sIL-6R, linked through a flexible peptide chain to IL-6 (Hyper IL-6). The concentration of Hyper IL-6 needed to arrest the growth of F10.9 cells was much lower than that needed of a combination of IL-6 and sIL-6R, added separately. Hyper IL-6 was also more active than IL-6 in stimulating growth of murine plasmacytoma T1165 cells, the half maximal stimulation being obtained at 2 pM Hyper IL-6 versus 23 pM for IL-6. In order to evaluate the effect of the fused sIL-6R/IL-6 proteins on human hematopoietic primitive progenitor cells, they were added to suspension cultures of CD34+ cells from human cord blood in addition to both flt3/flk2 ligand (FL) and stem cell factor (SCF). Fused sIL-6R/IL-6 produced a marked stimulation of cell expansion and a marked increase in the number of colony forming units when subsequently plated in semi-solid medium with IL-3, GM-CSF, SCF and erythropoietin. Ex-vivo maintenance and expansion of early progenitor cells in bone marrow transplantation protocols may be a potential application for the sIL-6R/IL-6 chimeric glycoproteins.

Endogenous Basic Fibroblast Growth Factor Displaced by Heparin From the Lumenal Surface of Human Blood Vessels Is Preferentially Sequestered by Injured Regions of the Vessel Wall

Abstract: Background Proliferation of smooth muscle cells (SMCs) of the arterial wall in response to local injury is an important factor in vascular proliferative disorders. Among the growth factors that promote SMC proliferation is basic fibroblast growth factor (bFGF), which is characterized by a high affinity for heparin and is associated with heparan sulfate on cell surfaces and extracellular matrices. We investigated whether heparin can displace endogenous active bFGF from the lumenal surface of blood vessels, whether bFGF is preferentially bound to injured blood vessels, and whether a synthetic, polyanionic, heparin-mimicking compound (RG-13577) can prevent sequestration of bFGF by the vessel wall. Methods and Results Injured and noninjured saphenous vein segments were perfused with or without heparin, in the absence or presence of 125I-bFGF and/or RG-13577 (a polymer of 4-hydroxyphenoxy acetic acid). Heparin displaced bFGF from the lumenal surface of the vein, and the released bFGF stimulated proliferation of SMCs. Likewise, systemic administration of heparin during open heart surgery resulted in a marked increase in plasma bFGF levels. Injured veins sequestered 125I-bFGF to a much higher extent than noninjured vein segments, both in the absence and presence of heparin. This sequestration was inhibited by compound RG-13577. Conclusions Despite its beneficial effects, heparin may displace active bFGF, which subsequently may be preferentially deposited on injured vessel walls, thus contributing to the pathogenesis of restenosis. This effect may be prevented by a synthetic heparin-mimicking compound.

Massive pericardial effusion complicating the course of chronic graft-versus-host disease (cGVHD) in a child with acute lymphoblastic leukemia following allogeneic bone marrow transplantation

Abstract: The pathogenesis and clinical features of chronic graft-versus-host disease (cGVHD) resemble those of several autoimmune diseases, as evidenced by frequent dermal, hepatic, occular, oral, pulmonary, gastrointestinal and neuromuscular involvement Serosal involvement, however, has only rarely been reported and most of the existing accounts are historical We describe a boy transplanted in third CR of CALLA-positive ALL from his HLA-identical sister who developed cGVHD, which was complicated by a huge pericardial effusion as a part of severe polyserositis including pleural effusion, ascites, and polyarthritis The patient shared the HLA antigens HLA-A2, B51, and DQW6 which are associated with autoimmune diseases

Major salivary gland dysfunction in patients with hematological malignancies receiving interleukin-2-based immunotherapy post-autologous blood stem cell transplantation (ABSCT)

Abstract: lnterleukin-2 (IL-2) is known to cause xerostomia and skin manifestations similar to graft-versus-host disease (GVHD). We therefore evaluated major salivary gland function in patients with hematological malignancies treated with IL-2 and interferon-alpha (IFN-alpha) after ABSCT. Eleven patients (seven male, four female) of median age 40 (24-47) were evaluated, seven with non-Hodgkin lymphoma (NHL); one with Hodgkin's disease (HD) and three with acute myelogenous leukemia (AML). Parotid and submandibular salivary gland function was assessed before, during and after IL-2/IFN-alpha administration by evaluation of the salivary flow rate and the composition of secreted saliva. Significant reductions in both the resting and stimulated parotid and submandibular salivary flow rates were observed during IL-2/IFN-alpha immunotherapy compared with the pre- and post-therapy values (P < 0.01), while no hyposalivation was observed in the control patients who underwent ABSCT and did not received IL-2. Sialochemical evaluation revealed a significant increase in potassium concentration (24.4+/-0.6 mEq/l to 28.9+/-1.4 mEq/l) and a significant decrease in sodium concentration (6.7+/-2.1 mEq/l to 3.3+/-1.0 mEq/l) (P < 0.05) in the stimulated parotid gland saliva secreted during IL-2/IFN-alpha administration. Salivary protein concentrations were not altered by the IL-2/IFN-alpha immunotherapy. Similar changes were previously observed in mice and humans with chronic GVHD. We conclude that IL-2 immunotherapy induces major salivary gland dysfunction in humans, similar to our previous observations in patients with chronic GVHD, which may indicate similar pathophysiologic mechanisms.

Soluble interferon-gamma receptor and interferon-gamma in patients undergoing allogeneic bone marrow transplantation for hematological malignancies.

Abstract: Interferon-gamma (IFN-gamma) is known to be involved in graft rejection of solid organs and acute graft-versus-host disease (GVHD). Its role, and especially that of soluble IFN-gamma receptor (sIFN-gamma R), in bone marrow transplantation (BMT) has not been established. We evaluated the sera of 27 patients following BMT. Fourteen of them underwent uneventful BMT, whereas 13 developed transplant-related complications, including acute GVHD (n = 5), early rejection (n = 4), or relapse of basic disease (n = 4). Soluble IFN-gamma R and IFN levels were evaluated at day -10 (preconditioning), day 0 (day of BMT), day of engraftment, and during BMT-related complications using sIFN-gamma R-specific monoclonal antibodies (McAB) followed by double-sandwich ELISA, and a sensitive radioimmunoassay respectively. In normal controls (n = 80) sIFN-gamma R and IFN-gamma levels in the sera were 0.5 +/- 0.05 and 0.3 +/- 0.04 ng/ml respectively. Soluble IFN-gamma R levels increased in direct correlation with engraftment (0.63 +/- 0.11 ng/ml at the day of BMT to 1.43 +/- 0.16 ng/ml at the day of engraftment; n = 14; P < 0.001). IFN-gamma levels increased in direct correlation with engraftment (0.37 +/- 0.03 ng/ml at the day of BMT to 5.69 +/- 1.64 ng/ml at the day of engraftment; n = 14; P < 0.001). In five patients with GVHD sIFN-gamma R levels increased from 0.43 +/- 0.19 ng/ml at the day of BMT to 1.73 +/- 0.17 ng/ml (P < 0.004) at the time of GVHD. Similarly, IFN-gamma levels increased from 0.43 +/- 0.08 ng/ml at the day of BMT to 3.03 +/- 0.5 ng/ml at the time of GVHD (P < 0.05). Both graft rejection and early relapse were associated with an elevation of IFN-gamma levels. In short, both s-IFN-gamma R and IFN-gamma were found to be significantly elevated during engraftment and GVHD. Hence these cytokines may be used as a tool for assessing engraftment and AGVHD.

Isradipine for the prevention of cyclosporine-induced hypertension in allogeneic bone marrow transplant recipients: a randomized, double-blind study.

Abstract: Background. Hypertension and nephrotoxicity frequently occur in patients who receive cyclosporine therapy after bone marrow transplantation (BMT). Isradipine, a calcium channel entry blocker, has been used successfully in cyclosporine-induced hypertension. Methods. Thirty leukemic patients who received cyclosporine after BMT were randomized to receive isradipine (0.005 mg/kg) from 72 hr before commencement of cyclosporine therapy until day 100 after BMT or placebo. Results. The placebo and isradipine groups were well matched. No differences were found between the isradipine and placebo groups in the level of blood pressure, renal function, marrow engraftment, or mortality. Hypertension incidence was surprisingly low (30% a week after hospital discharge and 10% by day 100 after BMT), and did not differ between the groups. Conclusions. Isradipine does not harm immunohematopoietic reconstitution after BMT; therefore, it may be used in this setting, although the previously reported incidence of hypertension has been exaggerated.

Activated long-term peripheral blood cultures as preparation for adoptive alloreactive cell therapy in cancer patients.

Abstract: Different modes of in vitro activation of peripheral blood mononuclear cells (PBMC) were compared for their effect on long-term propagation. PBMC cultures were activated by short exposures to the mitogen phytohemagglutinin (PHA) and the CD3 complex, with or without secondary signals provided by ligands of CD28 costimulatory molecules. Activation and long-term cultures were carried out in the presence of recombinant interleukin-2 (rIL-2). Addition of supernatant derived from IL-2-activated PBMC improved culture cell yield. Cumulative fold expansions ranged between 10(3) and 10(5) within 21 days. The highest cell yield was found after PHA activation. Fewer cells were obtained after activation with a combination of CD3 and CD28, and even fewer were obtained after CD3 activation alone. An increase in CD8+ and CD56+ cells, without change in CD4+ cells, was found in activated cultures when compared with fresh PBMC. Non-MHC-restricted cytotoxic activity was documented in all activated cultures. Cytotoxic activity per culture was highest in PHA-activated PBMC because of the high cell yield on the day of harvest. Successful in vitro expansion of PBMC might be helpful for gene transfer into T lymphocytes, as well as for the induction of an antitumor response, particularly for prevention and treatment of relapse of hematologic malignancies following allogeneic or autologous bone marrow transplantation.

Nedocromil sodium ameliorates skin manifestations in a murine model of chronic graft-versus-host disease

Abstract: Dermal fibrosis, loss of cutaneous appendages, and loss of subcutaneous fat are the main manifestations of chronic graft-versus-host disease (cGVHD) in mice. Mast cells (MC) may have a role in cGVHD. To investigate this point we have evaluated the effect of a MC stabilizer (nedocromil sodium) and a MC activator (compound 48/80) on skin manifestations in a murine model of cGVHD (B10.D2-->BALB/c). Mice were treated with nedocromil sodium (5 mg/day) or compound 48/80 (10 micrograms/day) from day -3 until day 15. Nedocromil ameliorated the skin features of cGVHD while compound 48/80 caused skin changes reminiscent of mild cGVHD in control mice. In addition nedocromil normalized peritoneal MC numbers and skin MC numbers and their activation state in the cGVHD mice. On the other hand compound 48/80 caused a complete disappearance of toluidine blue stainable peritoneal MC from cGVHD and control mice and decreased skin MC in controls. In summary, MC activation may play a negative role in the skin changes seen in cGVHD while MC stabilization ameliorates the skin manifestations of cGVHD and therefore may have a therapeutic benefit.

Noncardiogenic Pulmonary Congestion following Bone Marrow Transplantation

Abstract: We report a 36-year-old female who developed acute pulmonary congestion as the first presenting sign of venoocclusive disease (VOD), complicating an otherwise successful bone marrow transplantation (BMT). Left ventricular function was normal by echocardiography. Conservative therapy included oxygen, Lasix, and low dose dopamine. Hepatic toxicity, the typical presenting feature of VOD, occurred in our patient 72 h after pulmonary congestion. VOD occurs in 20-50% of BMT patients and is the result of widespread endothelial damage as a result of chemoradiotherapy. The dominating clinical feature is liver toxicity. Pulmonary manifestations of VOD have not been described as presenting features, and in fact have been noted as rare and late sequelae of BMT. Therefore, in the setting of preserved left ventricular function, acute pulmonary congestion early after BMT may represent the onset of VOD.

A comparison of the safety and efficacy of ondansetron versus granisetron as prophylaxis against chemo/ radiotherapy-induced nausea and vomiting in bone marrow transplantation patients. A double-blinded, randomized, prospective, pilot study

Abstract: Introduction. Nausea and vomiting (N&V) are well known and distressing side effects of chemoradio therapy. Conditioning protocols for patients undergo ing bone marrow transplantation (BMT) consist of highly emetogenic high-dose chemotherapy with or without total body irradiation (TBI). The 5HT3 (sero tonin receptor) antagonists heralded a marked im provement in controlling chemotherapy-induced N&V. Ondansetron and granisetron have been avail able for some time with limited information available concerning their pharmacological and pharmacoeco nomic differences and patient acceptability.Patients and Methods. This pilot study initiated comparison of the two drugs and evaluated the antiemetic efficacy and safety of a single daily dose of ondansetron, 16 mg, plus dexamethasone, 10 mg, compared to granisetron, 3 mg, plus dexamethasone, 10 mg, in patients receiving high dose chemotherapy (±TBI), prior to BMT. The 12-month pilot study was double-blinded, randomized, and prospective. A non- homogenous cohort of 2...

Enhancement of megakaryocytopoiesis by Campath-1G-treated natural killer cells

Abstract: Campath-1G is a CD52 (rat IgG2b) moAb used in bone marrow transplantation (BMT) to prevent graft-versus-host disease (GVHD) by the elimination of T cells via antibody-dependent cell cytotoxicity (ADCC) in vivo. We have previously reported that Campath-1G induces T cell proliferation, activation, and production of cytokines which in turn causes an enhancement of megakaryocytopoiesis in vitro. In view of the fact that recent studies have indicated that natural killer (NK) cells may also be involved in the regulation of megakaryocytopoiesis, we undertook the study of the in vitro effect of Campath-1G-treated NK cells on the regulation of megakaryocytopoiesis. Early burst-forming BFU-MK and late colony-forming CFU-MK were grown from 2 × 105 peripheral blood non-adherent mononuclear cells (NAMC) in plasma clots in the presence of aplastic canine plasma (PICS-J) which was used as megakaryocyte colony-stimulating factor (MK-CSF). The first step in elucidating this series of events was to investigate the direct influence of NK cells on megakaryocytopoiesis. Co-culturing NK cells (>85% CD16+) with autologous NAMC at a ratio of 1:1 resulted in a significant increase in the proliferation of CFU-MK and BFU-MK over NAMC cultured alone. This effect was further enhanced upon exposure of NK to Campath-1G (0.1–3 μ g/ml). To investigate the possible influence of soluble factors released from NK cells treated with Campath-1G on MK maturation, conditioned medium (CM) derived from Campath-1G-treated-enriched populations of NK cells was found to enhance MK progenitor growth. Our data demonstrate that resting and Campath-1G-treated NK may be involved in the immunomodulation of megakaryocytopoiesis.

Cytokine-mediated immunotherapy following autologous bone marrow transplantation in lymphoma and evidence of interleukin-2-induced immunomodulation in allogeneic transplants.

Abstract: PURPOSE Relapse remains a major problem following treatment of hematologic malignancies and metastatic solid tumors with allogeneic and autologous bone marrow transplantation (alloBMT and autoBMT). Our goal was to introduce posttransplantation immunotherapy for eradication of tumor cells that escape high-dose chemoradiotherapy prior to transplantation. PATIENTS AND METHODS Murine B-cell leukemia in BALB/c mice was used to develop a preclinical model to study the role of cytokine-mediated immunotherapy and allogeneic cell-mediated immunotherapy with donor lymphocytes in minimal residual disease (MRD). Based on these studies, a clinical trial was initiated to investigate the safety and efficacy of treating lymphoma patients with recombinant interleukin-2 (rIL-2) and interferon-alpha (IFN-alpha) at the stage of MRD following autoBMT. The clinical application of donor lymphocyte infusion (DLI) was also investigated for treatment and prevention of relapse following alloBMT. Patients in relapse following alloBMT who were resistant to DLI were treated with DLI plus rIL-2 in an attempt to activate the alloreactive potential of immunocompetent donor lymphocytes. RESULTS High-dose rIL-2 was effective against MRD in BALB/c mice, and the combination of rIL-2 and IFN-alpha resulted in synergistic effects even at doses of rIL-2 that were ineffective when given alone. In this animal model, graft-versus-leukemia/lymphoma (GVL) effects were induced by DLI after alloBMT and could be potentiated by coadministration of rIL-2. In clinical studies, rIL-2 plus IFN-alpha significantly improved relapse rate and survival in lymphoma patients treated after autoBMT. Relapse following alloBMT was successfully treated with DLI, and a proportion of patients who failed to respond to DLI could be salvaged with a combination of DLI and low-dose rIL-2. CONCLUSIONS Following autoBMT, GVL effects may be induced with a combination of rIL-2 and IFN-alpha, resulting in a reduced rate of relapse. The combination of both allogeneic donor lymphocytes and rIL-2 seemed synergistic. Because DLI plus rIL-2 was effective, even following failure of myeloablative conditioning, future strategies for treatment of leukemia should be based on T-cell-dependent immunotherapy rather than high-dose chemoradiotherapy.

Human umbilical cord blood myeloid progenitor cells are relatively chemoresistant: a potential model for autologous transplantations in HIV-infected newborns.

Abstract: Vertical transmission from mother to child occurs in 15-39% of women infected with the human immunodeficiency virus (HIV). Stem cell transplantation has recently been suggested as a potential therapy for patients with HIV infection. We have examined the possible advantages of human cord blood (HUCB) stem cells over bone marrow (BM) stem cells in the treatment of HIV-infected newborns. HUCB myeloid progenitors were found to be statistically more resistant to interferon-alpha (IFN-alpha), cytarabine (ARA-C), and eilatin than BM myeloid progenitor cells grown with IL-3 (P < 0.05). HUCB treated with IFN-alpha, ARA-C, and eilatin demonstrated a significantly higher capacity for self-renewal manifested by delta assay following 7 days in liquid culture. We, therefore, suggest that HUCB purged by anti-HIV drugs may be a source for autologous transplantation in HIV-infected newborns.

Should soybean agglutinin purging be performed in breast cancer patients undergoing autologous stem cell transplantation? a retrospective analysis of 48 patients

Abstract: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) has gained an increasing role in the treatment of high-risk Stage II-III and/or metastatic breast cancer patients. Several investigators reported on a high rate of tumor cells contaminating the bone marrow and peripheral blood stem cell collection. Nevertheless, the clinical implication of reinfusion of tumor cells with the stem cells to the relapse rate is still uncertain. In this retrospective analysis we compare the outcome and the toxicity of 29 patients with high-risk Stage II-III and 19 metastatic breast cancer patients who underwent HDC with ASCT. Thirteen patients underwent transplant with soybean agglutinin (SBA)-purged graft, while 35 consecutive patients received unmanipulated graft. Engraftment was significantly faster for the nonpurged transplant. No differences in disease-free survival, freedom from relapse, or overall survival were noted in both groups during a median follow up time of 14 months. We conclude that tumor cell purging using SBA in breast cancer patients is not warranted. New purging methods are needed to assess the role of tumor cell purging in breast cancer patients.

Impaired liver function tests in patients treated with antithymocyte globulin : implication for liver transplantation

Abstract: Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n = 16;p < 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n = 16;p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n = 16;p < 0.036), and then declined to 121.9 ± 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n = 16;p < 0.44) and then declined to 46.0 ± 14 (n = 16;p < 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n = 16;p < 0.02), and were 168.0 ± 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μM I-1 to 22.7 ± 2.8 (n = 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.

The putative role of arylsulfatase in interleukin-2- mediated cytotoxicity and interleukin-7-mediated bactericidal activity of natural killer cells

Abstract: We have examined the cytolytic and bactericidal activity of resting and cytokine-stimulated natural-killer (NK) cells against K562 and Daudi cell lines and Escherichia coli, respectively. Unstimulated NK cells showed considerable cytolytic activity against K562 (64±4%) and relatively low activity against the Daudi cell lines (22±9%). Pretreatment of NK cells with the arylsulfatase (AS) type-II-specific inhibitor NaH2PO4 reduced cytotoxicity towards K562 and Daudi 1.3- and 2.9-fold (p 0.05;n=12) and 1.2-fold towards Daudi (p>0.05;n=12) indicating that AS does not participate in IL-2-mediated NK cytolytic activity against these cell lines. IL-7 (3 units/ml) did not cause any enhancement of NK cytolytic activity. Unstimulated NK cells showed considerable bactericidal activity against E. coli (23±4%). Incubation of resting NK cells with NaH2PO4 reduced the bactericidal effect only by 1.09-fold (p>0.05;n=12), indicating that AS does not mediate this effect. IL-2 (200 units/ml) and IL-7 (3 units/ml) enhanced the bactericidal activity 1.5- and 2.2-fold, respectively (p 0.05;n=8). In contrast, IL-7 showed significant enhancement of AS release in resting or f-MLP-induced NK cells (36±3% vs 22±2% and 49±3% vs 29±2%, respectively) (p<0.05;n=8).

Correlation Between Chronic Graft-vs-HOST Disease, Mast Cell Degranulation and Fibrosis

Abstract: Graft-vs-Host disease (GVHD) is believed to result from the reaction of donor immunocompetent T-cells against alloreactive antigens of the host. Chronic GVHD (cGVHD), both in humans and in mice, is an autoimmune-like phenomenon resembling idiopathic scleroderma. The etiology of cGVHD seems to be multifactorial and the precise nature of both effector cells as well as their molecular targets, have not yet been completely elucidated. It was previously demonstrated that in a murine model of cGVHD obtained by irradiating Balb/c mice followed by injection with splenocytes of B10D2 mice (across minor histocompatibility barriers), connective tissue mast cells (MC) are completely degranulated just before fibrosis development [1]. MC have been implicated in a number of fibrotic diseases [2]. We have recently demonstrated that activated MC can enhance fibroblast proliferation and collagen synthesis in an in vitro MC, fibroblast culture system [3].