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Biomedical subjects

R Parkman

Publications and source records attributed to R Parkman.

At least 73 records · Page 4Linked to original sources
PubMed1987

Molecular heterogeneity of a lymphocyte glycoprotein in immunodeficient patients.

Previous evaluation of lymphocytes taken from patients with Wiskott-Aldrich syndrome (WAS) and other X-linked immunodeficiencies has revealed deficiencies of a lymphocyte sialoglycoprotein with a relative molecular mass of 115 kD (designated gpL-115) found in normal lymphocytes. The development of monoclonal antibodies to gpL-115 has permitted the detection of molecular heterogeneity in gpL-115 from the lymphocytes of immunodeficient patients. When lymphocytes from normal individuals were analyzed by immunoblotting, gpL-115 with only a single molecular species (115 kD) was detected. Lymphocytes from 17 immunodeficient patients were analyzed after overnight incubation. Two patients had no gpL-115 with an Mr of 115 kD, but gpL-115 with an Mr of either 95 or 135 kD was detected. Nine patients had gpL-115 with Mr equally of 95 and 115 Kd. Other patients exhibited gpL-115 with combinations of 95, 115, and 135 kD. The heterogeneity of the degraded gpL-115 suggests that WAS and other X-linked immunodeficiencies are due to a series of abnormalities, all of which involve gpL-115, and may explain the clinical heterogeneity of the diseases.

Animals↗
PubMed1986

Morphology and lytic mechanisms of interleukin 3-dependent natural cytotoxic cells: tumor necrosis factor as a possible mediator.

Populations of interleukin 3 (IL 3)-dependent cells can be derived from mouse bone marrow that display natural cytotoxicity (NC) against Wehi-164 target cells but do not display natural killing against YAC-1 cells. These bone marrow-derived NC cells cultured up to 2 mo in IL 3 do not contain rearranged T cell receptor beta-chain genes. They appear to be mast-like cells by electron microscopy and contain heterogeneous type granules. The molecules that mediate NC appear to be contained in these granules and are preformed because protein synthesis inhibitors have no effect on the capacity of IL 3-dependent NC cells to lyse Wehi-164 target cells. In addition to the IL 3-dependent bone marrow-derived cells, the basophilic leukemia cells, RBL-1, but not P815 mastocytoma cells were found to mediate NC against Wehi-164 cells. Both bone marrow-derived NC and RBL-1 cells can lyse L929 cells in 18 hr, suggesting that the putative NC mediator may be related to lymphotoxin/tumor necrosis factor (TNF). Recombinant human TNF displayed identical properties as NC cells; both entities possessed the same target cell specificity and had similar kinetics of target cell killing. The use of polyclonal rabbit antimouse TNF antibody blocked the actions of NC cells. Thus we believe that the mediation of NC is through the actions of a TNF-like molecule.

Animals↗
PubMed1986

Current status of bone marrow transplantation in pediatric oncology.

Histocompatible bone marrow transplantation (BMT) is the treatment of choice for pediatric patients with second remission acute lymphoblastic leukemia or acute myelogenous leukemia (AML) and has been successfully used to treat patients with first remission AML and stable-phase chronic myelogenous leukemia. The principle causes of transplantation failure are recurrent leukemia and therapeutic toxicities, including idiopathic interstitial pneumonitis and graft versus host disease (GVHD). The likelihood of leukemic relapse is related primarily to the remission status of the patient; patients in first remission have a lower relapse rate than patients in second remission, and the relapse rate of both is less than that of patients in relapse. Interstitial pneumonitis is due, in part, to the total body irradiation (TBI) that is used to cytoreduce the patients. TBI administration has been modified to reduce its toxicity. Acute and chronic GVHD are due to the immuno-aggression of donor T-lymphocytes against recipient non-HLA antigens. The in vitro removal of the T-lymphocytes from the donor bone marrow inoculum reduces the incidence of acute and chronic GVHD but may have the adverse effect of reducing hematopoietic engraftment and increasing leukemic relapse since the graft versus leukemia effect may be eliminated. The expanding role of BMT includes its use in the treatment of nonleukemic neoplasms (neuroblastoma, solid tumors) and the use of histoincompatible BMT for eligible patients without histocompatible donors.

Bone Marrow Transplantation↗
PubMed1986

The application of bone marrow transplantation to the treatment of genetic diseases.

Genetic diseases can be treated by transplantation of either normal allogeneic bone marrow or, potentially, autologous bone marrow into which the normal gene has been inserted in vitro (gene therapy). Histocompatible allogeneic bone marrow transplantation is used for the treatment of genetic diseases whose clinical expression is restricted to lymphoid or hematopoietic cells. The therapeutic role of bone marrow transplantation in the treatment of generalized genetic diseases, especially those affecting the central nervous system, is under investigation. The response of a generalized genetic disease to allogeneic bone marrow transplantation may be predicted by experiments in vitro. Gene therapy can be used only when the gene responsible for the disease has been characterized. Success of gene therapy for a specific genetic disease may be predicted by its clinical response to allogeneic bone marrow transplantation.

Animals↗
PubMed1986

Clonal analysis of murine graft-vs-host disease. I. Phenotypic and functional analysis of T lymphocyte clones.

Acute and chronic graft-vs-host disease (GVHD) due to non-MHC histocompatibility differences differ histopathologically. Acute GVHD is characterized by the cytotoxic destruction of recipient tissues, whereas chronic GVHD is characterized by increased collagen deposition. In an attempt to determine if acute and chronic GVHD represent two phases of the same pathophysiologic process or two distinct processes, the T lymphocytes from the C57BL/6 (B6) recipients of LP spleen cells (non-H-2 GVHD) have been cloned and compared to clones from immune mice (LP anti-B6). Acute GVHD (G) clones were established on day 10-14 posttransplant and chronic GVHD (CG) clones on day 50 from animals with clinical chronic GVHD. Immune (I) clones were established 10 to 14 days after immunization. All I clones exhibited B6-specific blastogenesis and cytotoxicity and had a Thy-1.2+, Lyt-2.2+, L3T4- phenotype. All CG clones were noncytotoxic, had I-Ab-specific blastogenesis, and had a Thy-1.2+, Lyt-2.2-, L3T4+ phenotype. The acute GVHD (G) clones were heterogeneous. Fourteen of 23 clones exhibited B6-specific blastogenesis and had a Lyt-2.2+, L3T4- phenotype (B6-G clones). Seven of 9 B6-G clones were cytotoxic for B6 targets. Nine of 23 G clones exhibited I-Ab-specific blastogenesis, and all but one clone had a Lyt-2.2-, L3T4+ phenotype as the did CG clones. Thus, the principal clonogenic T lymphocytes from mice with acute and chronic GVHD differ in terms of 1) their antigenic specificity, 2) their cytotoxic capacity, and 3) their surface phenotype. The presence of I-Ab-specific T lymphocytes with a phenotype identical to CG clones early after transplantation suggests that the immunologic events that result in chronic GVHD begin soon after transplantation. These results indicate that acute GVHD is due primarily to recipient-specific cytotoxic donor T lymphocytes, whereas chronic GVHD is due to autoreactive helper T lymphocytes.

Acute Disease↗
PubMed1986

Clonal analysis of murine graft-vs-host disease. II. Leukokines that stimulate fibroblast proliferation and collagen synthesis in graft-vs. host disease.

T lymphocyte clones were established from mice with acute and chronic graft-vs-host disease (GVHD) [C57B6/6 (B6) mice transplanted i.v. with LP/J spleen cells] and immune mice (LP/J mice immunized intraperitoneally with B6 spleen cells). To determine the role of leukokines in the increased collagen production that characterizes chronic GVHD, the supernatants of in vitro stimulated clones were assayed for their effect on 1) B6 embryonic fibroblast proliferation, 2) total fibroblast collagen secretion, and 3) collagen secretion per fibroblast. Four of nine chronic GVHD (CG) clones stimulated both total collagen secretion and collagen secretion per fibroblast, but none stimulated fibroblast proliferation. Six of 10 immune (I) clones stimulated fibroblast proliferation, and none stimulated collagen secretion per fibroblast. Acute GVHD (G) clones were heterogeneous; 2/10 G clones stimulated fibroblast proliferation, 5/10 stimulated total collagen secretion, and 4/10 stimulated collagen secretion per fibroblast. I and CG clones may act synergistically in vivo. The presence of CG-like clones in mice with acute GVHD suggest that the immunologic events that culminate in chronic GVHD are initiated early after transplantation.

Acute Disease↗
PubMed1986

The selective growth of murine newborn-derived suppressor cells and their probable mode of action.

Naturally occurring suppressor cells residing in the spleens of newborn mice of less than 5 days old are known to suppress various lymphocyte activities. A population of these suppressor cells can be maintained and expanded in the supernatants derived from Wehi-3 cells. These suppressor cells, designated as Wehi-3-expanded neonatal splenocytes (WENS), can suppress mixed lymphocyte reactions (MLR) and T and B cell mitogen responses without any genetic restrictions. The WENS bear the Ly-5, J11d, and class I molecules. WENS suppression is not mediated through an interleukin 1 or interleukin 2 absorptive mechanism. To achieve maximum suppression of MLR, WENS must be present for at least 24 hr. WENS inhibited the proliferation of Wehi-164 cells but not other tumor cells. The inhibition of Wehi-164 growth was due to the action of natural cytotoxic cells, because WENS lysed Wehi-164 cells but not the natural killer target cell YAC-1. Maximum lysis of Wehi-164 by WENS required 18 to 24 hr. Five WENS cell lines were cultured for more than 6 mo; three of the cell lines lost their capacity to lyse Wehi-164 targets (natural cytotoxicity) and simultaneously lost their natural suppressor activity. The two WENS lines that retained natural cytotoxicity also retained natural suppressor activity. Thus, natural suppressor cells may manifest their suppression through a natural cytotoxicity mechanism.

Animals↗
PubMed1986

Antibody-treated bone marrow transplantation for patients with severe combined immune deficiency.

Histocompatible bone marrow transplantation is the treatment of choice for patients with severe combined immunodeficiency (SCID). Patients without histocompatible donors have been treated with a variety of nontransplant therapies; however, normal immunocompetence has not been achieved. Bone marrow transplantation with untreated histoincompatible bone marrow has resulted in fatal graft-versus-host disease and/or no lymphoid engraftment. Based upon murine experiments, the use of monoclonal antibody- and complement-treated parental bone marrow has been used to successfully transplant SCID patients. Monoclonal antibodies to a variety of T-lymphocyte differentiation antigens (OKT-3, T-12, CT-2, and Leu-1) have been used. The antibody-treated transplants differ in several important respects from histocompatible transplants for SCID. Many recipients for treated marrow grafts require immunosuppression. In certain cases, hematopoietic stem cell ablation with total body irradiation (TBI) or busulfan has been required to achieve stable lymphoid engraftment although the biological basis for the requirement for hematopoietic stem cell elimination is unclear. The use of antibody-treated parental bone marrow is the most effective form of therapy for patients with SCID who do not have a histocompatible donor.

Antibodies, Monoclonal↗
PubMed1986

Morphological abnormalities in the lymphocytes of patients with the Wiskott-Aldrich syndrome.

Lymphocytes from 18 patients with the Wiskott-Aldrich Syndrome (WAS) were examined by scanning electron microscopy (SEM). Most peripheral blood lymphocytes from normal individuals are covered with slender microvillus projections, but a large proportion of lymphocytes from WAS patients were found to be relatively devoid of microvilli. A lymphocyte morphology scoring system was developed to quantify the density of microvilli: Grade 4 classified those lymphocytes with greater than 75% of the surface covered with microvilli with progressive decrements to grade 1, which were those without microvilli. The mean lymphocyte morphology score of eight normal individuals was 3.62 +/- .22. The mean lymphocyte score of WAS patients was substantially lower (2.89 +/- .27, P less than .001). In addition, WAS lymphocytes often were qualitatively abnormal, with short, blunted microvilli. These morphological criteria were used to diagnose WAS from the cord blood lymphocytes of one "at-risk" patient. Thus, WAS is the first primary immunodeficiency in which morphological abnormalities have been identified that can aid in diagnosis.

Cell Membrane↗
PubMed1985

Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes.

Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.

Actuarial Analysis↗
PubMed1984

Characterization of a human lymphocyte surface sialoglycoprotein that is defective in Wiskott-Aldrich syndrome.

gpL115 is a lymphocyte surface component that is deficient in patients with the X-chromosome-linked immune deficiency Wiskott-Aldrich syndrome (6). The glycoprotein nature of gpL115 is demonstrated through labeling in carbohydrate moieties by [3H]NaBH4 and its synthesis by lymphocytes through labeling with [35S]methionine. Native gpL115 adheres to wheat germ lectin-Sepharose and sialidase-treated gpL115 does not adhere, indicating that native gpL115 adheres via clusters of sialic acid residues. When tested on peanut lectin, which shows specificity for the disaccharide Gal beta 1-3GalNAc, gpL115 is nonadherent and sialidase-treated gpL115 is adherent, indicating the presence of the sequence sialic acid-Gal beta 1-3GalNAc, which is characteristic for O-linked (mucin-type, acidic-type) carbohydrates. A surface glycoprotein with all the above characteristics was found on the lymphoblastoid cell line CEM. CEM cells were used as immunogen to generate the monoclonal antibody L10, an IgG1, which binds native and sialidase-treated gpL115 . Sialidase-treatment of gpL115 significantly alters its physical properties, reducing its electrophoretic mobility and changing its behavior on isoelectrofocusing. Cumulatively, these findings indicate that gpL115 , like glycophorin of erythrocytes and GPIb of platelets, is a sialoglyco protein with significant quantities of O-linked carbohydrate. On treatment with limiting sialidase concentrations, gpL115 of normal lymphocytes is transformed into a series of partially desialylated species of decreasing electrophoretic mobility. This finding resembles the situation with lymphocytes of some Wiskott-Aldrich syndrome patients. Lymphocytes of eight Wiskott-Aldrich syndrome patients were found to be deficient in 125I-labeled gpL115 . Lymphocytes from three of these patients displayed an abnormal 125I-component of apparent mol wt 135,000.

Antibodies, Monoclonal↗