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Biomedical subjects

R Parkman

Publications and source records attributed to R Parkman.

At least 91 records · Page 5Linked to original sources
PubMed1984

Heparin inhibition of antibody-dependent complement-mediated lysis.

The effect of heparin on the monoclonal antibody-dependent complement-mediated lysis of human lymphoid cell lines and peripheral blood T-lymphocytes was studied. T-lymphoid cell lines (CEM and MOLT-3) were lysed by optimal concentrations of monoclonal antibodies and rabbit complement. Heparin at concentrations as low as 0.5 U/ml partially inhibited the complement-mediated lysis of all antibody-cell combinations while a heparin concentration of 25 U/ml produced complete inhibition. Lysis mediated by an IgG monoclonal antibody (J5) to the common acute lymphoblastic leukemia antigen (CALLA) was more sensitive to heparin inhibition than that due to an IgM antibody (VIL A1). Bovine and porcine heparin were equally inhibitory. Peripheral blood T-lymphocytes collected in heparin (100 U/ml) were resistant to complete lysis when treated with 17F12 and complement immediately after isolation; complete lysis was achieved only when they were incubated for 2 h prior to treatment. The role of monoclonal antibody and complement in the in vitro lysis of normal and leukemic lymphocytes is discussed.

Animals↗
PubMed1984

Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation.

The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.

Adolescent↗
PubMed1983

The pathophysiology and treatment of graft-versus-host disease.

Acute and chronic GVHD remain major impediments to the wider application of allogeneic marrow transplantation. It is presumed that human acute GVHD is analogous to the murine model which is initiated by donor T lymphocytes reacting with recipient 'minor' histocompatibility antigens. Chronic GVHD may result from immunoaggression of donor lymphoid cells that have developed and differentiated within the host. Lack of GVHD (i.e., the development of tolerance) may be due either to generation within the host of specific suppressor lymphocytes or to clonal deletion of alloreactive donor cells. Over the last five years progress has been made in the recognition, early diagnosis and successful therapy of chronic GVHD. Methods of prevention and therapy of acute GVHD are still largely unsuccessful. With improved understanding of immune regulation, it is hoped that GVHD can be eliminated in patients transplanted for non-malignant conditions and adroitly modified (without loss of anti-leukaemic potential) in patients with malignant disorders. The challenge of the coming decade is to reach these goals while speeding the return of full immunological competence in the marrow transplant recipient.

Acute Disease↗
PubMed1983

Acute and chronic graft-versus-host disease induced by minor histocompatibility antigens in mice.

We have developed a murine model of acute and chronic forms of graft-versus-host disease (GVHD) as defined by clinical features that develop in response to minor histocompatibility antigen (minor HA) differences. C57BL/6J (B6) and LP/J mice were selected for serologic identity at H-2 and for mutual nonreactivity in mixed lymphocyte culture (MLC). Lethally irradiated B6 recipients were transplanted with anti-Thy-1.2-treated LP bone marrow cells plus various numbers of untreated LP spleen cells. The B6 recipient mice developed acute and chronic forms of GVHD that showed clinical and histological similarities to the acute and chronic forms of GVHD seen in human recipients of bone marrow transplants from HLA-identical and MLC-nonreactive donors. The definition of acute and chronic GVHD by clinical criteria appears to have biological significance in predicting subsequent survival patterns of recipient mice with GVHD. The incidence of acute and chronic GVHD in the mouse model was a function of the number of donor spleen cells transplanted. Using this model, we demonstrate that both acute and chronic forms of GVHD are initiated by donor lymphocytes. Based on these results, acute and chronic forms of GVHD induced to minor HA appear to be two manifestations of the same T-cell-mediated disease process rather than two different diseases.

Acute Disease↗
PubMed1983

Immature T lymphocytes in the peripheral blood of bone marrow transplant recipients.

Recipients of allogeneic bone marrow transplants are characterized by an immunodeficiency of varying intensity and duration. We have previously demonstrated the presence of in vivo activated suppressor T lymphocytes in immunodeficient patients with chronic graft-versus-host disease. To determine the basis of the immunodeficiency of transplant recipients early after transplantation, the lymphocytes of transplant recipients were analyzed phenotypically by E-rosette formation and staining with monoclonal antibodies (OKT-3, -6, and -8) and functionally by their blastogenic response to mitogens. Only 15% of transplant recipients' assays 0-3 months and 16% of assays 3-12 months following transplant were in the normal range. Transplant recipients during the first year after transplantation were characterized by an increased percentage (57%) of patients with a normal percentage of E-rosette-forming cells but reduced PHA responsiveness. In vitro coculture experiments demonstrated that their lack of PHA responsiveness was not due to the presence of in vivo activated suppressor cells or a decrease in mitogen-presenting cells. Staining with monoclonal antibodies revealed that the T lymphocytes from the majority of recipients at 0-3 months following transplantation contained a percentage of OKT8-positive cells greater than or equal to the percentage of OKT3-positive cells. This pattern (OKT8 greater than or equal to OKT3) was not found in the peripheral blood T lymphocytes of normal people but was found in 13 of 15 thymuses. Monoclonal staining with OKT6, a thymocyte-specific antibody, revealed positive staining of more than 10% of the peripheral blood leukocytes in the majority of recipients 0-3 months following transplantation, compared with only a few normals. We concluded that the circulating T lymphocytes of transplant recipients are phenotypically and functionally immature, and that their relative immaturity contributes to the transplant recipients' immunodeficiency.

Antibodies, Monoclonal↗
PubMed1983

Regulation of human immunoglobulin E synthesis in acute graft versus host disease.

Immunoglobulin (Ig) E synthesis was studied in vitro in eight patients who had received transplants of allogeneic bone marrow. Seven of these patients developed acute graft vs. host disease (GVHD) and elevated serum IgE levels, whereas the eighth did not. In vitro synthesis of IgE, but not of IgG, was elevated in cultures of lymphocytes obtained during acute GVHD (17,923 +/- 14,607 pg/10(6) cells) but not in cultures of lymphocytes obtained after resolution of the acute GVHD when the serum IgE had returned to normal (106 +/- 31 pg/10(6) cells). In contrast, lymphocytes from the patient with no acute GVHD, like normal lymphocytes, failed to synthesize IgE in vitro. The increased in vitro IgE synthesis in acute GVHD was suppressed by normal allogeneic lymphocytes and by autologous lymphocytes obtained after the resolution of the acute GVHD, but not by allogeneic lymphocytes obtained from patients undergoing acute GVHD. The deficiency in functional IgE-specific suppressor cells in acute GVHD occurred in the face of normal or increased percentages of circulating T8+ cells, which in normal subjects contain the IgE-specific suppressor cells. In two patients studied, there was evidence of activated IgE-specific, circulating helper T cells. T cells from these two patients, but not normal T cells, secreted spontaneously upon culture in vitro a factor that induced IgE, but not IgG, synthesis by normal B cells. Finally, a survey of 21 bone marrow transplant recipients revealed that acute GVHD was a necessary requirement for the development of elevated serum IgE levels in recipients of bone marrow transplants. These results suggest that acute GVHD is accompanied by an imbalance in IgE-specific immunoregulatory T cells consisting of activated helper T cells and deficient suppressor cells.

Acute Disease↗
PubMed1983

Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia.

We performed a prospective randomized trial of antithoracic duct lymphocyte globulin (ATDLG), HLA-haploidentical marrow, and androgen (regimen ABA) versus androgen alone (concurrent STANDARD care controls) in 42 newly diagnosed individuals with severe aplastic anemia. ABA patients also were matched with patients from our preceding study (historical STANDARD care controls). Supportive care and pretreatment patient characteristics were the same in all groups. By life table analysis, 76% of patients receiving ABA are alive at 2 yr compared to 31% of the concurrent control group (p less than 0.002 versus ABA) and 19% of the historical controls (p less than 0.0001 versus ABA) given STANDARD care. ABA patients had greater hematologic improvement than either control group (p less than 0.001). However, improvement with ABA was often incomplete. Toxicity of ATDLG was considerable but manageable. Further studies to determine the mechanism of action and active component(s) of ABA are indicated.

Androgens↗
PubMed1982

Kinetics of the anti-recipient cytotoxic cell response of mice with minor histocompatibility antigen graft-vs-host disease.

The kinetics of the anti-recipient cytotoxic cell response of spleen cells from mice undergoing graft-vs-host disease (GVHD) induced to minor histocompatibility antigens were studied. Two population of cytotoxic cells were identified. Cytotoxic T lymphocytes (CTL) were present in recipient spleens 2 and 3 wk after transplantation but disappeared from the spleens before the onset of clinical disease. Cytotoxic T lymphocyte precursors (CTLp) were first detected in recipient spleens 2 wk after transplantation and were present during clinical disease. CTL may function as effectors in GVHD induced to minor histocompatibility antigens.

Animals↗
PubMed1982

Comparison of cell-mediated lympholysis and mixed lymphocyte culture in the immunologic evaluation for renal transplantation.

We investigated the relationship between both pre-transplant cell-mediated lympholysis assay (CML) and mixed lymphocyte culture (MLC) and transplant outcome (graft function and survival) in 33 living, related donor renal transplants performed during the past 5 yr. Both assays were excellent predictors of transplant outcome. A positive CML assay was correlated with the occurrence of early acute rejection episodes (p less than 0.005), shortened time to graft dysfunction (serum creatinine greater than 1.5 mg/dl) (p less than 0.001), and poor long-term graft survival (p = 0.07). Similarly, a positive MLC was correlated with acute rejection episodes (p less than 0.005), graft dysfunction (p = 0.001), and poor graft survival (p less than 0.01). To determine the relative prognostic significance of the CML and MLC assays, we compared the correlation of each of them with the occurrence of acute rejection episodes. Under a logistic model of probability, the CML and MLC assays were equally predictive of an early acute rejection episode (p less than 0.01); however, the combination of CML and MLC together improved the accuracy of the prediction of an acute rejection episode by 50%. These results indicate that the CML and MLC assays are independent predictors of transplant outcome and that both tests should be an integral part of the immunologic evaluation of prospective living, related donors for renal transplantation.

Adolescent↗
PubMed1981

Histiocytosis-X.

Twelve of 17 patients with histiocytosis-X were immunologically abnormal, as shown by the presence of circulating lymphocytes spontaneously cytotoxic to cultured human fibroblasts or of antibody to autologous erythrocytes. The patients also had a notable lack of histamine H2 surface receptors on their T lymphocytes, suggesting a suppressor-cell deficiency. The lymphocyte abnormalities were reversed in vitro after incubation in a crude extract of calf thymus gland, and therefore all 17 patients were treated with daily intramuscular injections of this extract. With this therapy, 10 patients entered complete remission -- a response at least as good as that observed in historical controls treated with chemotherapy. A positive clinical response was associated with an increase in the number of T-cell histamine H2 receptors to normal levels and with correction of the other immunologic abnormalities. The results of this preliminary study justify a larger prospective clinical trial of thymic extract and further investigation of the immunoregulatory mechanisms in histiocytosis-X.

Cell Membrane↗
PubMed1981

A patient with post-hepatitis B immune deficiency: nonspecific helper factor partially restores the in vitro immune response.

A patient with severe post-hepatitis B aplastic anemia had depressed B and T cell responses. In mixed leukocyte culture, her cell were unresponsive to unrelated control stimulating cells, but responded well to a pool of cells from the same unrelated controls. She had reduced production of lymphocyte mitogenic factor (MF), suggesting a helper cell defect, and she had few or no cells reactive with the monoclonal anti-T cell antibodies OKT3, OKT4 or OKT5. Her cells proliferated in response to MF produced by a pool of cells without mitogen, however. Furthermore, her cells became specifically cytotoxic when stimulated by cells plus MF, but not when stimulated by either cells or MF alone. Thus her T cell deficiency was correctable by nonspecific helper factor in vitro.

Adolescent↗
PubMed1981

Anti-recipient cytotoxic T lymphocyte precursors are present in the spleens of mice with acute graft versus host disease due to minor histocompatibility antigens.

A model for bone marrow transplantation across minor histocompatibility barriers was developed by using mouse strains that were H-2 identical and mutually non-reactive in MLC. Acute graft-vs-host disease was induced only when donor lymphoid cells were included in the marrow inoculum, in both C57BL/6 recipients of LP cells and BALB/c recipients of B10.D2/nSN cells. GVHD was prevented by treating the lymphoid cells with anti-Thy 1.2 and C before transplantation. Spleen cells from mice with acute GVHD were not directly cytotoxic to recipient strain target cells. However, when spleen cells from mice with GVHD were boosted in vitro to recipient strain stimulator cells they generated a specific anti-recipient cytotoxic response. Spleen cells from mice without GVHD did not generate a cytotoxic response in vitro. The cytotoxic effector cells and their precursors were shown to be T lymphocytes. This model and the in vitro method described may be useful in further studies of the immunobiology of GVHD due to minor histocompatibility antigens and of transplantation tolerance.

Acute Disease↗
PubMed1981

Cellular basis of autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is produced by the in vivo destruction of red cells coated with auto-antibodies which are produced by naturally occurring B-lymphocytes. The auto-antibody-producing cells are under the control of suppressor T-lymphocytes whose activity may be deficient in patients with AIHA. The ultimate cure of AIHA will probably reside in the reestablishment of the normal control of the autoantibody-producing cells and not in the elimination of the cells responsible for the destruction of the antibody-coated cells by splenectomy or drug therapy. The cells responsible for destruction of red cells are necessary for the removal of other antibody-coated particles (such as bacteria, etc.). The removal or inactivation of tissue macrophages predisposes the patient to other serious problems including the possibility of serve sepsis. The reestablishment of normal control of the auto-antibody-producing cells by the normalization of the patient's suppressor cell status may be a safer mode of therapy for autoimmune hemolytic anemia in the future.

Anemia, Hemolytic, Autoimmune↗