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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 217 records · Page 12Linked to original sources
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

Use of recombinant human interleukin-2 in conjunction with bone marrow transplantation as a model for control of minimal residual disease in malignant hematological disorders: I. Treatment of murine leukemia in conjunction with allogeneic bone marrow transplantation and IL-2-activated cell-mediated immunotherapy.

Immunotherapy with recombinant human interleukin-2 (IL-2) and allogeneic spleen cells has led to significant antitumor effects in B-cell leukemia- (BCL1) bearing mice following transplantation with T-lymphocyte-depleted allogeneic bone marrow cells. Graft versus leukemia (GVL) effects were studied in a model mimicking minimal residual disease following bone marrow transplantation (BMT). Lethally irradiated (BALB/c x C57BL/6)F1 recipients were reconstituted with 20 x 10(6) T-lymphocyte-depleted C57BL/6 bone marrow cells mixed with 10(4) to 10(6) BCL1 cells followed by administration of sequential increments of allogeneic C57BL/6 spleen cells; 10(6) cells on Day +1, 10(7) cells on Day +5, and 5 x 10(7) cells on Day +9, with or without concomitant IL-2 treatment (intraperitoneal injections of 20,000 U twice daily for 3 days) together with each spleen cell administration. All mice receiving 10(4)-10(6) BCL1 cells developed marked splenomegaly by Day +21 and all adoptive recipients of 10(5) spleen cells obtained from these mice developed leukemia within 21-36 days. Treatment of mice which received 10(4) BCL1 cells by either three courses of low dose IL-2 or three increments of allogeneic spleen cells alone and certainly by a combination of both resulted in normalization of splenomegaly on Day +21, but only adoptive recipients of 10(5) spleen cells obtained from mice treated by both allogeneic spleen cells and IL-2 (10/10) or allogeneic spleen cells alone (8/10) were disease free (greater than 100 days). Mice inoculated with 10(5) BCL1 cells developed mild splenomegaly on Day +21 after IL2 treatment alone, but showed no clinical evidence of disease following administration of allogeneic spleen cells or both allogeneic spleen cells and IL-2. Following adoptive transfer of 10(5) spleen cells obtained from each treated group no leukemia (greater than 100 days) was evident in recipients of spleen cells obtained from mice treated with both allogeneic spleen cells and IL-2 (10/10) whereas a partial effect was observed in mice treated by allogeneic spleen cells only (4/10). Mice inoculated with a high dose of BCL1 cells (10(6] showed some delay in onset of splenomegaly, but no curative antileukemic effects could be observed even following a synergistic combination of IL-2 and allogeneic spleen cells. Our data suggest that immunocompetent allogeneic lymphocytes may play an important role against leukemic relapse and thus cell therapy may be used therapeutically to treat minimal residual disease after BMT even following initial reconstitution with T-cell-depleted bone marrow cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
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

Radiosensitivity and responsiveness to recombinant interleukin-2 of effector cells of graft vs. host disease and mixed lymphocyte reaction in mice.

Synergistic effects of recombinant interleukin-2 (IL-2) or irradiated spleen cells were investigated in vivo and in vitro. Irradiated (750 cGy) C57BL/6 spleen cells infused to sublethally irradiated (500 cGy) BALB/c mice treated with IL-2 (1,000 U 3 times/day) caused graft vs. host-like disease (GVHD) in 3 of 11 mice. Similarly irradiated allogenic spleen cells caused no GVHD in irradiated recipients not administered IL-2. No sign of autologous GVHD was found in mice that received irradiated syngeneic spleen cells with IL-2. Addition of recombinant IL-2 in vitro to mixed lymphocyte reactions (MLR) using irradiated (500 cGy) allogeneic responder spleen cells augmented the 3H-TdR uptake fourfold compared to cultures without IL-2, but was 44-fold below the allogeneic response of nonirradiated C57BL/6 spleen cells. Il-2-induced cell proliferation was also noted in syngeneic MLR, but did not lead to GVHD in in vivo experiments. The data suggest that IL-2 may potentiate GVHD and alloreactivity induced by an adequate number of irradiated, nondividing but viable allogeneic spleen cells and/or that secretion of IL-2 by alloactivated T lymphocytes, supplied exogenously in the present study, may play a role in the GVHD syndrome. Since neither viable but nonreplicating T cells nor IL-2 alone caused GVHD, it is suggested that endogenously produced IL-2 by alloactivated T lymphocytes may be important in the development of the GVHD syndrome, independent of its main function of enhancing T lymphocyte proliferation. On the other hand, the lack of GVHD following administration of high numbers of irradiated or nonirradiated syngeneic spleen cells with IL-2 implies that allogeneic T lymphocytes and not IL-2 activated MHC-nonrestricted cytotoxic cells play a role in inducing the GVHD syndrome in vivo.

Animals↗
PubMed1992

The role of recombinant cytokines and other immunomodulators on engraftment following allogeneic bone marrow transplantation in mice.

BALB/c mice were conditioned by total body irradiation (TBI) with a suboptimal (475 cGy) or optimal (600 cGy) radiation dose for induction of chimerism subsequent to administration of 10(7) (BALB/c x C57BL/6) F1 (F1) bone marrow cells in order to test whether a variety of recombinant cytokines and other immunomodulators caused positive or negative effects on engraftment at different time intervals post-bone marrow transplantation (BMT). Engraftment in recipient mice conditioned by the minimal dose of TBI permitting 100% induction of chimerism (600 cGy) was not impaired following treatment with recombinant human interleukin 2 (IL2) (10(4) Cetus Units x 3/day i.p.), alpha interferon (alpha IFN) (10(4) units/day i.p.), gamma interferon (gamma IFN) (10(4) U/day i.p.) and combinations of IL2 + alpha IFN as well as IL2 + gamma IFN given either 5 days prior to or 5 days following BMT. Likewise, neither PGE2 (50 micrograms x 2/day i.p.) nor indomethacin (25 micrograms x 2/day i.p.) given either immediately prior to or immediately following BMT for 3 consecutive days had any detectable effect on chimerism. To investigate the putative beneficial effects of IL2 in enhancing marrow engraftment, BALB/c mice were irradiated with a suboptimal dose of TBI (475 cGy) followed by reconstitution with 10(7) F1 marrow cells supplemented with 2 x 10(6) F1 spleen cells. IL2 (10(4) U x 3/day i.p. x 5 days) was administered either prior to TBI, between TBI and BMT, immediately following BMT, or starting 2 weeks post-BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial.

OBJECTIVE: To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: A prospective, open-label study. SETTING: Inpatient metabolic units of four university medical centers. PATIENTS: Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. INTERVENTION: After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms. MAIN RESULTS: Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01). CONCLUSION: Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Barrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow.

Murine hematopoietic bone marrow is heterogenous in respect to bone-lining cells, hematopoiesis, and release of blood cells. In diaphyseal femoral marrow, bone-lining cells are largely osteoblasts, indifferent endosteum, blood cells, and reticular cells. Hematopoiesis is sustained by rather differentiated progenitors, as myelocytes and polychromatophilic erythroblasts. But in sharply restricted loci within trabeculated bone in the distal medial femoral metaphysis, bone-lining cells are dominated by newly discovered fibroblastic, contractile, stromal barrier cells; activated, multilaminar and branched, enveloping putative stem cells; and extending into the marrow, where they enclose hematopoietic clusters of rather early progenitors, as promyelocytes; and basophilic erythroblasts. Barrier cells may endocytize granules released individually by vicinal differentiating granulocytes, preventing tissue damage. Barrier cells envelope blood vessels and insinuate processes into their wall, augmenting blood-marrow barriers, preventing release of immature cells. Further, extensions of venous sinuses made of extraordinarily thin barrier cell processes receive released blood cells. With heightened hematopoiesis due to mutant hemolytic anemias or after administration of interleukin-1, barrier cells and their associated structures are greatly increased, spreading beyond normally restricted loci. But in microenvironment-deficient mutants, barrier cells are fewer, less activated, and less granulated. Barrier cells thus appear important in hematopoiesis and in the release of blood cells from bone marrow.

Animals↗
PubMed1991

Mother and son with deletion of 3p25-pter.

We report on a mother and son with a 3p25-pter deletion. Both have postnatal growth retardation, mental retardation, apparently low-set or malformed ears, and telecanthus. The mother also has ptosis and multiple joint pains, while the son has a long philtrum and anteverted nares. These phenotypes are compared to those of other 3p- patients. Both patients have many manifestations previously described. The son appears to be more severely affected than the mother.

Abnormalities, Multiple↗
PubMed1991

Comparative study of in vitro inhibition of activation of the classical and alternative pathways of human complement by the magnesium and sodium salts of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA).

The inhibitory activity of the sodium salt of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA) on activation of the classical and alternative pathways of human complement was compared with that of the clinically used magnesium salt of NAAGA (NAAGA-Mg). Sodium salt of NAAGA (NAAGA-Na) inhibited both pathways of activation in a dose-dependent manner at concentration ranging from 1 to 10 mM by acting on formation and/or function of the C3 convertases as shown by the inhibitory capacity of the peptide on the release of the C3 cleavage fragment C3b and C3a. NAAGA-Na was as effective as NAAGA-Mg in inhibiting classical pathway activation at concentration above 10 mM. NAAGA-Na was more effective than NAAGA-Mg in inhibiting the alternative pathway since the sodium salt did not interfere with Mg-dependent formation of the alternative pathway C3 convertase.

Animals↗
PubMed1991

Deformation-driven, lethal damage to cancer cells. Its contribution to metastatic inefficiency.

Direct and indirect, in vivo and in vitro observations are in accord with the hypothesis that as a consequence of their deformation within capillaries, cancer cells undergo sphere-to-cylinder shape-transformations that create a demand for increased surface area. When this demand cannot be met by apparent increases in surface area accomplished by nonlethal, surface "unfolding," the cell surface membrane is stretched; if expansion results in more than a 4% increase in true surface area, the membrane ruptures, resulting in cancer cell death. It is suggested that this deformation-driven process is an important factor in accounting for the rapid death of circulating cancer cells that have been trapped in the microvasculature. Therefore, this mechanism is thought to make a significant contribution to metastatic inefficiency by acting as a potent rate-regulator for hematogenous metastasis.

Animals↗
PubMed1991

Effects of doxorubicin on the sensitivity of L1210 leukemia cells to deformation-associated trauma.

Most of the cancer cells arrested in the microcirculation during hematogenous metastasis are rapidly killed; one major mechanism is surface-membrane rupture, associated with the mechanical deformation of cancer cells in capillaries. The feasibility of increasing the susceptibility of cancer cells to lethal, deformation-associated trauma by doxorubicin, was tested in an in vitro mechanical model system, by filtering suspensions of L1210 leukemia cells through 8-microns pore-size Nuclepore membranes, with or without prior incubation with 10(-7)M doxorubicin. The results showed that mechanically-induced loss of cancer cells immediately after filtration was increased from 18 to 55% in cells previously exposed to doxorubicin for 48 h. The results indicate the feasibility of chemotherapeutic enhancement of the mechanical killing-action of the microvasculature as a potential rate-regulator of hematogenous metastasis.

Animals↗
PubMed1991

Barrier cells in the spleen.

Barrier cells are a newly defined group of activated fibroblastic cells that are deployed as diverse barriers in the splenic pulp. The central capacity of the spleen, namely clearance of the blood, is normally modest but when stressed, for example by infectious disease, imperfect blood cells or the administration of interleukin 1, the clearance capacities of the spleen expand. The normally scarce barrier cells rapidly and greatly increase in number in splenic stress. By augmenting the splenic filtration beds, regulating blood flow, enveloping white pulp and enclosing hematopoietic colonies, they appear to be important in the spleen's increased capacities in clearance, phagocytosis, immunological reactivity and hematopoiesis. This review focuses on their role in the spleen, but barrier cells may appear throughout the body in response to needs for walling off and cellular induction.

Animals↗
PubMed1991

Autosomal dominant crystalline dystrophy.

A black woman was identified with a tapetoretinal degeneration with sparkling intraretinal crystals, retinal pigment epithelial and choroidal atrophy, night blindness, color vision abnormalities, and paracentral scotomas. This constellation of findings is most consistent with the diagnosis of Bietti's crystalline dystrophy. Eight other family members were identified with intraretinal crystals similar to those seen in the proband but in varying degrees of progression. Transmission electron microscopy of circulating lymphocytes in several patients demonstrated crystals and granular osmophilic material of unknown composition contained within abnormal lysosomes. These crystals are similar in appearance and location to those seen in cholesterol ester storage disease. This family demonstrates an autosomal dominant inheritance pattern, as well as other differences from classic Bietti's crystalline dystrophy. The authors, therefore, suggest that this new entity be named autosomal dominant crystalline dystrophy.

Adult↗
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

Quantitative microscopy of mouse colon 26 cells growing in different metastatic sites.

Quantitative microdensitometry and computerised interactive image analysis were used to compare the expression of endogenous lectins by cells of mouse colon 26 carcinomas, growing either as primary tumours or metastases, in five different anatomic sites (caecum, liver, lung, spleen, s.c.). Endogenous lectins were visualised in tissue sections using the ABC peroxidase technique with a panel of 17 biotinylated neoglycoproteins representing a variety of carbohydrates found in glycoproteins, glycolipids and proteoglycans. Clear-cut site-associated differences in endogenous lectin expression were detected in cancer cells growing in all five sites. The patterns of these changes were complex and shifts in expression of different lectins were independently variable in both direction and amount. In addition to site-associated variations, differences in lectin expression were also detected in the liver and lungs, between cells in spontaneous metastases and cells in colonies generated by direct injection of cancer cells into the bloodstream. The results demonstrate quantitative, as distinct from qualitative, differences developing in cancer cell populations after delivery of cells to different target organs. The differences between liver and lung metastases are in accord with analogous site-associated differences in metastatic patterns produced by colon carcinoma cells in mice and in humans.

Animals↗