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Biomedical subjects

R Or

Publications and source records attributed to R Or.

At least 181 records · Page 10Linked to original sources
PubMed1992

Effects of interleukin 2 on engraftment following autologous bone marrow transplantation (ABMT) in dogs.

Beagle dogs were treated with recombinant human interleukin 2 (IL-2) 6 x 10(6) International Units (IU)/day for 7 consecutive days following conditioning with sublethal (200 cGy) or lethal (400 cGy) doses of high-dose rate whole body irradiation (WBI) and reconstitution with 2 x 10(8)/kg autologous bone marrow cells, in order to assess the effect of IL-2 on engraftment. Engraftment of dogs conditioned by lethal doses of WBI was not impaired following treatment with IL-2 6 x 10(6) IU/day. At an RIL-2 dose of 6 x 10(6) and 9 x 10(4) IU/day, enhanced engraftment of autologous bone marrow cells was observed in dogs irradiated with a sublethal WBI dose in comparison with controls not treated by IL-2(p < 0.05). We conclude that therapeutic doses of IL-2 may be safely utilized during hematopoietic reconstitution. Under certain conditions IL-2 may even enhance hematopoietic reconstitution following ABMT.

Animals↗
PubMed1992

Immunotherapy of minimal residual disease by immunocompetent lymphocytes and their activation by cytokines.

A murine model of minimal residual disease (MRD) was established utilizing the murine B-cell leukemia (BCL1). BALB/c mice inoculated with up to 10(4) BCL1 were cured (greater than 1 year disease-free survival) following administration of intraperitoneal injections of recombinant human IL-2 (10(5) Cetus units x 3/day intraperitoneally x 5 days). Lethally irradiated BALB/c or (BALB/c x C57BL/6)F1 recipients were reconstituted with syngeneic bone marrow cells or T-cell-depleted C57BL/6 bone marrow cells contaminated with 10(4), 10(5), or 10(6) BCL1 to simulate quantitative MRD. Untreated mice died of typical leukemia without exception, whereas a substantial anti-leukemia effect was noted in mice treated by allogeneic spleen cells, IL-2, or particularly a combination of allogeneic spleen cells and IL-2 given concomitantly. Increments of donor-type spleen cells (10(6), 10(7), and 5 x 10(7)) or IL-2 (10(4) U x 2/day x 3 days) were given alone or in combination on days +1, +5, and +9 following Thy 1.2-depleted allogeneic BMT. All adoptive recipients of 10(5) spleen cells obtained from mice inoculated with 10(4) and 10(5) BCL1 treated by a combination of allogeneic spleen cells and IL-2 showed no evidence of disease greater than 100 days. The antitumor effects of allogeneic spleen cells alone and IL-2 alone were also highly significant, although not totally curative in all mice. Allogeneic spleen cells seemed more effective as compared with low dose IL-2 (3 courses of 2 x 10(4) U x 2/day x 3 days). None of the recipients of 10(6) BCL1 could be completely cured under the experimental conditions described without additional chemotherapy, although significant antitumor effects could again be documented following concomitant administration of allogeneic spleen cells and IL-2. Using an experimental model of autologous BMT, recipients of 10(3) tumor cells could also be cured following transplantation of syngeneic spleen cells by high-dose IL-2 (10(5) U x 3/day x 5 days) given at the time lymphocytes were present, optimally at 3 weeks following BMT. Based on encouraging results from experiments using our animal model of MRD, in conjunction with autologous and allogeneic BMT, pilot clinical trials are currently underway, investigating the effect of cytokine-mediated immunotherapy (CMI) in MRD following conventional and high-dose cytoreductive anticancer therapy in conjunction with ABMT. In addition, we are attempting induction of cell-mediated cytokine-activated immunotherapy (CCI) in conjunction with autologous and allogeneic BMT. Prospective randomized clinical trials and longer observation periods are required to assess the full efficacy of these new therapeutic modalities.

Animals↗
PubMed1992

Glycosylated serum ferritin in patients with hematological malignancies before and after bone marrow transplantation.

Glycosylated and total serum ferritin levels were monitored in patients with acute leukemia and lymphoma undergoing bone marrow transplantation (BMT). Serum ferritin was high in relapsing patients and normal in most patients in complete remission (CR). In patients with an uncomplicated course, levels of ferritin increased during the first month after BMT with subsequent decrease. Three patients with lymphoma and five with acute leukemia had high serum ferritin levels despite achieving apparent complete hematological remission which was of short duration. The results were compared with groups of lymphoma patients at presentation and during remission and with healthy normal controls. In all the lymphoma patients and in 3 of the 5 leukemia patients the percent of ferritin glycosylation was normal at CR. It was low at the time of diagnosis in all patients. Thus, the percent glycosylation proved a more reliable marker for clinical remission than total serum ferritin. During follow up after BMT in uncomplicated cases, the percent of glycosylated ferritin returned to normal levels earlier than the total serum ferritin. These findings indicate that the evaluation of the amount of glycosylated ferritin may provide useful information in hematological patients in whom there is a discrepancy between high serum ferritin levels and the clinical condition.

Bone Marrow Transplantation↗
PubMed1992

Successful T cell-depleted allogeneic bone marrow transplantation in a child with recurrent multiple extramedullary plasmacytomas.

Multiple plasmacytomas with IgA paraproteinemia, a low grade lymphoid neoplasm of differentiated B cells rarely seen in the young, were encountered in a 10-year-old child. T cell-depleted allogeneic bone marrow transplantation (BMT) was performed because of progressive disease despite chemotherapy. Donor T cells were infused after transplantation in gradually increasing numbers to achieve a graft-versus-tumor effect. Complete eradication of all tumor masses was achieved following BMT with normalization of serum immunoglobulin levels. The patient remains in complete remission 4 years after BMT. Allogeneic BMT should be considered early in the course of low-grade lymphoid malignancy in the younger age group.

Bone Marrow Transplantation↗
PubMed1992

Immunotherapy of minimal residual disease in conjunction with autologous and allogeneic bone marrow transplantation (BMT).

Recent investigations in animal models of human lymphoid and myeloid leukemia suggest that induction of immune-mediated antitumor effects is feasible at the stage of minimal residual disease (MRD) using allogeneic immunocompetent lymphocytes following initial reconstitution with T cell depletion and/or activation of reconstituting syngeneic or allogeneic immune cells by recombinant interleukin-2 (rIL2). Pilot clinical trials in patients with leukemias and lymphomas at high risk to relapse following autologous bone marrow transplantation (BMT) suggest that beneficial antitumor effects may be achieved at the stage of MRD by home immunotherapy as soon as hematopoietic reconstitution occurs using rIL2 (Cetus) and alpha interferon (Roferon A) (Hoffmann LaRoche). Although results obtained from our open trial seem encouraging, prospective randomized trials and longer observation periods are needed in order to confirm immune-mediated antitumor effects in conjunction with autologous BMT in patients with malignant hematological disorders at high risk to relapse. Likewise, it seems that amplification of anti-leukemia effects following allogeneic BMT is feasible by post-transplant infusion of donor's peripheral blood lymphocytes for prevention and/or treatment of relapse.

Adolescent↗
PubMed1992

Neutropenic enterocolitis associated with autologous bone marrow transplantation.

Fatal neutropenic enterocolitis was seen in a patient undergoing autologous bone marrow transplantation for non-Hodgkin's lymphoma. Excessive drug action due to a mildly diminished creatinine clearance could have contributed to the pathogenesis. Computed tomographic scanning and ultrasonography demonstrated pneumatosis of the gastrointestinal tract, but the disease had become extensive by then. Necrotizing enterocolitis should be suspected early in a granulocytopenic patient with abdominal pain and diarrhea or vomiting. Aggressive surgical or medical management may avoid a fatal outcome.

Adult↗
PubMed1991

Charybdotoxin-sensitive, Ca(2+)-dependent membrane potential changes are not involved in human T or B cell activation and proliferation.

The involvement of ion channels in B and T lymphocyte activation is supported by many reports of changes in ion fluxes and membrane potential after mitogen binding. Human T and B lymphocytes demonstrate an early and transient hyperpolarization after ligand binding. Inasmuch as the change in membrane potential is dependent on elevation of free cytosolic calcium, the hyperpolarization is presumably through opening of Ca(2+)-stimulated K+ channels. We have used charybdotoxin, a known inhibitor of Ca(2+)-dependent K+ channels, to study the role of these channels in lymphocyte activation and mitogenesis. We demonstrate that charybdotoxin inhibits the ligand-induced transient membrane hyperpolarization in B and T cells in a dose-dependent fashion, without affecting changes in cytosolic Ca2+. However, blockade of the Ca(2+)-activated K+ channel is not associated with changes in cell-cycle gene activation, IL-2 production, IL-2R expression or B and T cell mitogenesis. These results imply that membrane potential changes secondary to the ligand-dependent opening of Ca(2+)-activated K+ channels are not involved in B and T lymphocyte activation and mitogenesis.

B-Lymphocytes↗
PubMed1991

EDTA-dependent pseudothrombocytopenia: a clinical study of 18 patients and a review of the literature.

EDTA-dependent pseudothrombocytopenia (EDTA-PTCP) is the phenomenon of a spurious low platelet count due to the appearance of antibodies that cause platelet agglutination in blood anticoagulated with EDTA. We review here the clinical features of 18 patients with EDTA-PTCP treated in our hospital from 1984 to 1987 as well as those of 34 patients reported in the literature. This phenomenon appears more frequently in severely ill patients, in association with autoimmune, neoplastic, atherosclerosis-related, and liver diseases. In the majority of our patients, EDTA-PTCP appeared during hospitalization, indicating that the antibody is an acquired one. Neither splenomegaly nor the presence of autoimmune markers were features of this entity. Unlike true thrombocytopenias, EDTA-PTCP is associated with a normal mean platelet volume. Awareness of this entity is essential since EDTA-PTCP is frequently misdiagnosed and therefore incorrectly treated.

Adult↗
PubMed1991

Treatment of pure red-cell aplasia following major ABO-mismatched T-cell-depleted bone marrow transplantation. Two case reports with successful response to plasmapheresis.

Major ABO-mismatched bone marrow transplantation (BMT) may be accompanied by red-cell haemolysis, but pure red-cell aplasia following BMT is a rare complication. Two cases of transient pure red-cell aplasia following T-lymphocyte-depleted BMT for a period of greater than 20 weeks are described, both of which responded to one cycle of plasmapheresis. The prompt response of the two patients described with red-cell aplasia with no evidence of haemolysis suggests that plasmapheresis may be considered in such clinical situations as a first treatment of choice before attempting more complex modes of therapy.

ABO Blood-Group System↗
PubMed1991

Control of relapse due to minimal residual disease (MRD) by cell-mediated cytokine-activated immunotherapy in conjunction with bone marrow transplantation.

In conclusion, lessons from the animal model of lymphoid leukaemia suggest that in the setting of allogeneic BMT, under certain conditions GVL effects may be separable from GVHD; more specifically, GVL effects may be induced despite development of tolerance of donor cells against allogeneic host alloantigens. The latter phenomenon suggests that either curative GVL effects may be inducible despite subclinical GVHD or alternatively that effector cells of GVL may recognize different tumour-associated targets different from cell surface determinants of 'normal' alloantigens. Alternatively, effector cells of GVL may be distinguished from effector cells of GVHD. It is tempting to suggest that NK and IL2-aspirated NK cells may play a major role as effector cells of GVL in an MHC non-restricted fashion, different from classical CD8+ cytotoxic cells that certainly play a major role in GVHD and GVL. Once proven, the latter hypothesis may help develop new and safer therapeutic approaches since NK cells and products of the NK cell family are unlikely to play a major role, if any, in GVHD. The feasibility of induction of GVL-like effects by MHC non-restricted effector cells, such as that observed by CMI, most likely through cytokine-activated NK cells, seems promising because such effector mechanisms may be utilized clinically through either adoptive transfer of in vitro-activated lymphocytes or activation of lymphocytes in vivo by administration of cytokines such as IL2 and alpha IFN. Similarly, induction of CCI following ABMT may permit establishment of GVL-like effects with no major risk of GVHD. Our animal models suggest that both approaches may be beneficial and perhaps even combined. From a practical standpoint, activation of antitumour effector cells in vivo is much more feasible, in comparison with the cumbersome and expensive technologies for large-scale in vitro manipulation of IL2-activated 'LAK' cells or tumour-infiltrating lymphocytes ('TIL') at dose ranges required for obtaining clinically meaningful responses. No less important is the fact that more potent immunotherapy may be inducible by cytokine combinations (such as IL2 and alpha IFN). We are currently investigating additional cytokine combinations in order to attempt to optimize antitumour effects inducible by allogeneic and syngeneic lymphocytes since it appears logical that amplifying in vivo antitumour responses by multiple cytokine combinations may yield better antitumour effects.

Animals↗
PubMed1991

Immunoglobulins A, G, and M to cytomegalovirus during recurrent infection in recipients of allogeneic bone marrow transplantation.

Occurrence and significance of specific IgA and IgM to cytomegalovirus (CMV) in recurrent CMV infection was evaluated in 21 allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) recipients who had been previously CMV seropositive. Of 17 patients with CMV infection, viruria was detected in 94%, CMV-specific IgA in 88% and IgM in 76%, and a fourfold rise in IgG in 65%. The median time between BMT and detection of viruria was 69 days, of IgA 70, of IgM 62, and of IgG 88 days. The IgM and IgA responses lasted for 14 and 30 days (median time), whereas high IgG titers persisted. Twelve patients developed CMV disease; in these the appearance of viruria, IgA, and IgM preceded the rise of IgG (P less than .02). CMV-specific IgA and IgM are valuable diagnostic tools in BMT recipients with recurrent CMV infection.

Adolescent↗
PubMed1991

Immune response to polio vaccination in bone marrow transplant recipients.

Following a small outbreak of poliomyelitis which occurred in the summer of 1988 in Israel, two sequential doses of inactivated polio vaccine (IPV) were administered to 42 bone marrow transplant (BMT) recipients (aged 2-50 years) who were 6-96 months (median 16 months) after transplantation. Prior to vaccination, only 68-80% patients (n = 42) had protective (greater than or equal to 4) antibody levels against the three serotypes of poliovirus, compared with 92-96% (n = 25) before BMT (p = 0.02 for types 1 and 3). After the second dose of IPV, 89-98% (n = 27) of the recipients had protective antibody levels. The pre-vaccination antibody titers were lower than before BMT (p = 0.006, 0.0007 and 0.0008 for types 1,2 and 3, respectively). After the first dose of IPV, antibody titers rose in the 42 patients (p = 0.002, 0.043 and 0.002 for types 1, 2 and 3, respectively) and following the second dose, a further increase in antibody levels was noted. Regression analysis revealed that graft-versus-host disease, pre-BMT polio antibody titers, age and type of transplantation (allogeneic versus autologous) were significant explanatory variables for the specific antibody levels, while the time lapse between BMT and vaccination, and primary disease proved of no significance. Vaccination against poliovirus after BMT is advocated, as it reinstates and raises the lost specific humoral immunity.

Adolescent↗
PubMed1990

Interstitial pneumonitis after total body irradiation: effect of partial lung shielding.

The potential beneficial effects of partial lung shielding were investigated in 44 patients conditioned by whole body radiotherapy as part of the conditioning for bone marrow transplantation (BMT). The first 23 patients were irradiated with fractionated total body irradiation (TBI) to a total dose of 12 Gy. In the second series of 21 patients a 50% transmission lung shield was utilized following 6 Gy TBI. This treatment was combined in the second group with four fractions of 1.5 Gy total lymphoid irradiation (TLI), given in 2 d. The rate of idiopathic interstitial pneumonitis (IP) was 26% in the first group, compared to none in the second.

Adolescent↗
PubMed1990

Effect of benign familial neutropenia on the periodontium of Yemenite Jews.

The purpose of this study was to compare the periodontal status of Yemenite Jews with and without benign familial neutropenia (BFN). Thirty-four volunteers were examined at baseline and after 3 years. Plaque index (PlI), bleeding index (BI) probing depth (PD), and attachment levels (AL) were recorded. Differential blood counts were done on at least three occasions during the study. Volunteers with at least one count of less than 2000 neutrophils were considered neutropenic. The majority of patients received oral hygiene instructions and scaling at the initial visit. During the study there was a significant drop in PlI (P less than 0.01) and BI (P less than 0.05). At baseline the BFN and non-BFN volunteers had similar PlI, but the BI was significantly greater in the BFN group. At follow-up, there was a significantly greater number of teeth with pockets greater than or equal to 6 mm in the BFN group (P less than 0.05). These results indicate that volunteers with BFN, a phenomenon that has not previously been associated with any pathology, are more susceptible to gingival inflammation and attachment loss than unaffected volunteers and that they respond more favorably to an improvement in oral hygiene.

Adult↗
PubMed1990

The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD?

Graft-versus-leukemia (GVL) is a major component of the overall beneficial effects of allogeneic bone marrow transplantation (BMT) in the treatment of leukemia. Although several clinical trials have suggested a direct relationship between GVL effects and acute and chronic graft-versus-host disease (GVHD), it is not yet known whether GVL can be separated from GVHD. However, several investigations in murine models of human leukemia indicate that the two may be at least partially separable. Moreover, analysis of clinical data from the International Bone Marrow Transplant Registry suggest that allogeneic BMT may be more advantageous than syngeneic BMT, regardless of the GVHD. Likewise, T lymphocyte depletion is associated with an increased incidence of relapse, independently of GVHD. Recent investigations in murine leukemia suggest that GVL-like effects may be inducible following syngeneic BMT by recombinant cytokines with no overt GVHD. Taken together, current data in experimental animals and man suggest that GVL may be at least partially separable from GVHD. Hence, further understanding of effector and target cells of GVL as well as our ability to induce antitumor effector cells, especially those that are MHC nonrestricted, may lead to new approaches for potentiating anti-tumor effector mechanisms without inducing severe, clinically overt GVHD. Successful attempts in these directions may also lead to improved results following autologous BMT as a result of activation of GVL-like effects by recombinant cytokines that are capable of activating effector cells with anti-leukemic activity in vivo, such as recombinant human IL2, alpha interferon or perhaps a synergistic combination of factors.

Animals↗