Bone marrow failure: immunologic implications and treatment modalities.
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Adult↗
Biomedical subjects
P Gascon
Publications and source records attributed to P Gascon.
Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo.
We have investigated interferon as a mediator of hematopoietic suppression in bone marrow failure. Interferon production by stimulated peripheral blood mononuclear cells from patients with aplastic anemia was significantly higher than that observed in controls; spontaneous interferon production by these cells was also high for more than half of aplastic anemia patients. Circulating interferon, not detectable in normal individuals, was detected in 10 of 24 patients. Interferon is a potent inhibitor of hematopoietic cell proliferation and, therefore, may be the mediator of suppression in many in vitro models employing patients' cells and sera. The possible pathogenic importance of interferon in aplastic anemia was suggested by an increase in hematopoietic colony formation in vitro after exposure of bone marrow cells to antiinterferon antisera (277 +/- 71% increase for patients compared to 1.6 +/- 1.6% for normal individuals). Interferon levels in the bone marrow sera of aplastic anemia patients were high (mean = 203 international units (IU)/ml, n = 8), even in comparison to circulating levels in the same patients. Normal bone marrow sera also contained measurable interferon but at lower levels (41 IU/ml, n = 16), indicating that interferon may be a normal bone marrow product. High concentration of bone marrow interferon, possibly due to abnormal immunologic activity or a reaction to virus infection of the bone marrow, may mediate hematopoietic suppression in aplastic anemia patients.
Anemia, Aplastic↗
Murine monoclonal antibodies to the myelin-associated glycoprotein react with large granular lymphocytes of human blood.
Monoclonal antibodies prepared to human myelin-associated glycoprotein were shown to react with a population of human peripheral blood mononuclear cells. The population is similar to the large granular lymphocytes or natural killer cells defined by antibody Leu 7 (also called HNK-1). The population also includes cells exhibiting the Leu 2 marker for suppressor/cytotoxic T cells. The results indicate a shared antigenicity between the nervous system and the immune system and may be relevant to the pathogenesis of demyelinating diseases.
Animals↗
A study of human serum sickness.
Twelve patients with bone marrow failure, who were undergoing therapy with daily intravenous infusions of horse antithymocyte globulin, were studied for the development of serum sickness. Eleven of 12 patients developed typical signs and symptoms of serum sickness 8-13 days after the initiation of treatment. These included fever, malaise, cutaneous eruptions, arthralgias, gastrointestinal disturbances, and lymphadenopathy. Eleven of 12 patients developed high levels of circulating immune complexes during serum sickness. All 12 patients also had concomitant decreases of serum C3 and C4 levels. In addition to urticarial and/or morbilliform eruptions, 8 of 11 patients also developed a serpiginous band of erythema along the sides of the fingers, hands, toes, or feet as an early cutaneous sign of serum sickness. Direct immunofluorescence of lesional skin biopsies during serum sickness revealed deposits of immunoglobulin or complement in the walls of small cutaneous blood vessels in 3 of 5 patients. These findings indicate that circulating immune complexes play a central role in the pathophysiology of human sickness.
Animals↗
Lymphokine abnormalities in aplastic anemia: implications for the mechanism of action of antithymocyte globulin.
Anti-thymocyte globulin (ATG) provides effective therapy for many patients with aplastic anemia, and its mechanism of action has been presumed to be secondary to lymphocytotoxicity. However, our studies of lymphocyte function in aplastic anemia show marked abnormalities of lymphokine production, which ATG may modulate. In 12 of 17 patients with aplastic anemia, interleukin 2 (IL2) production was markedly elevated in vitro (P less than .01 by paired statistical analysis). Expression of the IL2 receptor, or Tac antigen, on peripheral lymphocytes assessed by flow microfluorometry was also increased above the normal range in 11 of 15 cases. Studies of ATG suggested that it might act to stimulate lymphocyte function. In vitro, ATG is a mitogen, as measured by incorporation of 3H-thymidine into blood mononuclear cells; the response of cells to ATG from patients with aplastic anemia was exaggerated in comparison with normals. Cell proliferation was accompanied by production of IL2 to levels that were, in some cases, similar to those obtained with lectin stimulation. Finally, supernatants from lymphocytes cultured in the presence of ATG were able to replace adherent cells in providing growth factors for the support of nonadherent cells in methylcellulose hematopoietic colony assays. These results provide a mechanism for an "immunostimulatory" action of ATG in effecting hematopoietic response in some patients with aplastic anemia.
Adult↗
A prospective clinical and immunologic analysis of patients with serum sickness.
We prospectively evaluated the clinical and immunologic features of serum sickness in 12 patients with bone-marrow failure treated for 10 days with intravenous infusions of horse antithymocyte globulin. Eleven of the 12 patients had signs and symptoms of serum sickness 8 to 13 days after beginning therapy with antithymocyte globulin. Eleven patients (including 10 of 11 with signs and symptoms of serum sickness) acquired circulating immune complexes, with peak levels occurring at 10 to 12 days. Serum C4 and C3 levels fell precipitously, with nadirs on the 10th day. Plasma levels of C3a anaphylatoxin were elevated in the four patients in whom it was measured. Eight of the 11 patients with signs and symptoms of serum sickness had a characteristic serpiginous erythematous and purpuric eruption on the hands and feet at the junction of palmar and plantar skin. Direct immunofluorescence of skin lesions revealed immune deposits (IgM, IgE, IgA, or C3) in the blood vessels of three of five patients. This study documents the immunopathology of serum sickness in human beings and describes a cutaneous marker for the disease.
Adolescent↗
The function of lymphocytes in normal and suppressed hematopoiesis.
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Anemia, Aplastic↗
Antithymocyte globulin reacts with many normal human cell types.
Antithymocyte globulin (ATG) is frequently effective therapy for aplastic anemia. Its mechanism of action is often assumed to be upon a lymphocyte inhibitor of hematopoiesis. However, specificity for T lymphocytes would not be anticipated from consideration of the method of preparing ATG. In fact, using flow microfluorometry and fluorescence immunohistochemistry, we have found that ATG binds to virtually all circulating lymphocytes, granulocytes, and platelets, as well as to bone marrow cells. Extensive absorption of ATG with either granulocytes or lymphocytes does not eliminate reactivity with the opposite cells, indicating that ATG recognizes some distinct antigens on each cell type. Treatment of cells with ATG blocks the binding of monoclonal antibodies directed against either lymphocyte differentiation or histocompatibility antigens. ATG also binds to visceral tissues, including thymus and testis cell membranes and the nuclear and cytoplasmic components of tonsil, kidney, liver, breast, lung, and intestine. In vitro cytotoxicity of ATG was demonstrated for both T and non- T lymphocytes and platelets. Despite its name, ATG is not specific for a particular cell type, and it would be premature to conclude that its effect is mediated through a specific lymphocyte population.
Antigen-Antibody Reactions↗
Type III hyperlipoproteinemia associated with apolipoprotein E deficiency.
Subjects with type III hyperlipoproteinemia develop premature atherosclerosis and have hyperlipidemia due to an increase in cholesterol-rich very low density lipoproteins (VLDL) of abnormal electrophoretic mobility. Apolipoprotein E is a major protein constituent of VLDL and appears to be important for the hepatic uptake of triglyceride-rich lipoproteins. A new kindred of patients with type III hyperlipoproteinemia is described in which no plasma apolipoprotein E could be detected, consistent with the concept that type III hyperlipoproteinemia may be due to an absence or striking deficiency of apolipoprotein E.
Apolipoproteins↗
Endogenous opiate receptor ligand: electrically induced release in the guinea pig ileum.
Opiate receptors mediate the electrically evoked inhibition of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum. The electrically induced activation of the opiate receptor was produced by a prolonged simulation at 10 hertz and provides the first evidence that an endogenous opiate receptor ligand is released by nerve stimulation. The specificity of the phenomenon was demonstrated by the reversal obtained with the narcotic antagonists naloxone, naltrexone, and GPA 1843; GPA 1847, the (+)-isomer of 1843, did not cause reversal. The model system described should be useful for the study of the storage, synthesis, and release of endorphins.
Electric Stimulation↗
[Hemorrhages during cardiac surgery with extracorporeal circulation].
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Blood Coagulation Tests↗
Central retinal vein occlusion: review of management.
Central retinal vein occlusion is usually a disease of the elderly and is often associated with systemic vascular disease, e.g., hypertension, diabetes mellitus, arteriosclerotic vascular disease. Younger patients, especially those less than 45 years of age, with retinal vein occlusion should be evaluated carefully for the possibility of an underlying thrombotic tendency. The authors describe the ocular manifestations, pathogenesis, associated conditions, patient evaluation, and treatment of patients with central retinal vein occlusion.
Age Factors↗
Central retinal vein occlusion: report of two familial cases.
The authors report a 46-year-old father and 17-year-old son who each presented with unilateral central retinal vein occlusion (CRVO) and bilateral abnormalities of retinal vascular perfusion. The son presented with a nonperfused CRVO in the left eye, developed traction-rhegmatogenous retinal detachment treated with vitreous surgery, and developed prolonged arteriovenous filling in the retina of the fellow eye. The father presented with progressive CRVO in the right eye, developed choroido-vitreal neovascularization following laser treatment to create a chorioretinal anastomosis, underwent vitrectomy for retinal detachment and vitreous hemorrhage in that eye, and developed prolonged arm-eye and retinal arteriovenous circulation times in the fellow eye. An extensive evaluation (including hematological studies and imaging of the major vessels of the neck) failed to reveal a predisposing cause in either patient although echocardiography disclosed a mitral valve thrombus in the father. After institution of coumadin therapy, the circulatory parameters in the fellow eye of each patient improved.
Adolescent↗