Cellular engineering through marrow transplantation.
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Anemia, Aplastic↗
Biomedical subjects
R A Good
Publications and source records attributed to R A Good.
Evidence of persistent IgA/IgG circulating immune complexes associated with activation of the complement system in serum of a patient with common variable immune deficiency: anaphylactic reactions to intravenous gammaglobulin.
A 44 year old woman with common variable immunodeficiency developed severe anaphylactic reactions to intravenous gammaglobulin. Analysis of her serum prior to the infusion of gammaglobulin was thus analyzed and the tests revealed a complete absence of free IgA, presence of an IgG autoantibody to IgA, IgA-IgG circulating immune complexes, and depressed levels of hemolytic C3 associated with elevated levels of C3a and C3d. The IgA-IgG complexes did not clear from the circulation even after six months following cessation of gammaglobulin infusions. Analysis of the complexes isolated by sucrose density gradient ultracentrifugation showed that they bind to solid phase F(ab')2 anti-C1q, have a high molecular weight (greater than 19s), activate the complement (C) system via the classical pathway in vitro and are comprised of IgG and IgA. These data suggest that in this patient an autoantibody response to IgA was probably associated with persistent endogenous production of IgA yielding IgG-IgA circulating immune complexes and activation of the complement system. Although the patient has no free IgA and no surface IgA bearing B cells, her peripheral blood lymphocytes were shown to contain cells capable of secreting IgA. Low levels of IgM and IgG were detectable in her serum, and B cells bearing surface IgM, IgG and IgD were present in normal numbers in the blood.
Adult↗
Autologous mixed lymphocyte reaction in man. XII. Deficiency of the autologous mixed lymphocyte reaction in patients undergoing allogeneic bone marrow transplantation. Relationship with chronic graft-versus-host disease.
Peripheral blood mononuclear cells from 14 patients with acute leukemia or aplastic anemia undergoing allogeneic bone marrow transplantation were examined for the autologous mixed lymphocyte reaction (AMLR) between T and non-T cells and its relationship with chronic graft-versus-host disease (GVHD). Five of 6 patients with GVHD demonstrated deficiency of the AMLR, whereas only three of 8 patients with no evidence of chronic GVHD had deficient AMLR. The nature of underlying disease had no effect on the AMLR. The significance of these results is discussed.
Adolescent↗
An immunosuppressive myeloablative preparative regimen adequate for matched sibling transplant, inadequate in histoincompatible, T cell-depleted marrow cells in leukemia.
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Adolescent↗
Effects of nutrition on disease and life span. I. Immune responses, cardiovascular pathology, and life span in MRL mice.
Mice of the autoimmune, lymphoproliferative strain MRL/lpr and the congenic, nonlymphoproliferative strain MRL/n were fed one of six diets from weaning on-ward. These mice were sacrificed at 3 or 5 months of age. Low fat diets resulted in lower cholesterol and higher triglyceride levels than did cholesterol-containing high-fat diets. Caloric restriction of MRL/lpr mice was associated with an increased plaque-forming cell response to trinitrophenylated polyacrylamide beads, less lymphoproliferation, and less severe glomerulonephritis. Diet did not affect the incidence of autoimmune vasculitis in MRL/lpr mice sacrificed at 5 months. MRL/lpr mice fed a low-fat, calorically restricted diet from 5 months of age to death lived longer than mice which were fed ad libitum a cholesterol-containing, high-fat diet. At death, MRL/lpr mice fed the former diet had the autoimmune vasculitis which had been evident in mice killed at 5 months, whereas mice fed the latter diet, in addition to the vasculitis, had a high incidence of atherosclerotic lesions of intrarenal and aortic branch arteries.
Animal Nutritional Physiological Phenomena↗
In vitro immune response of cells of various lymphoid tissues in (NZB X NZW)F1 mice: evidence for abnormality of the mesenteric lymph node cells.
Autoimmune-prone (NZB X NZW)F1 (B/W) mice have been shown to have a variety of immunologic perturbations. However, most studies have been performed with spleen cells. By using the Mishell-Dutton culture system, we examined the in vitro immune response of the various lymphoid tissue to determine whether an imbalance at a selective lymphoid site may exist in B/W mice. It was shown that the ability of mesenteric lymph node (MLN) cells of B/W mice to generate plaque-forming cells (PFC) in response to sheep red blood cells was consistently less than that of the spleen cells. This relationship held true in the aged mice. In contrast, the ability of the MLN cells of other strains not prone to develop autoimmunity to generate PFC was higher than that of the spleen cells. No significant difference in the mitogenic response of the lymphoid cells from various lymphoid tissue in the young B/W mice was seen, as compared with normal lymphoid cells from control mice. However, it was demonstrated that a relative decrease of B cells and immunoregulatory Lyt-123+ cells in the MLN in the B/W mice occurred early in life, and it was concluded that this abnormality may account for the low PFC response observed.
Aging↗
Prostaglandins in cells of the lymphoid system in AKR leukemia.
AKR mice develop spontaneous lymphoid leukemia late (8 to 12 months) in life, although persistent murine leukemia virus production occurs throughout their life. This suggests that age-related changes are involved in development of leukemia. Prostaglandin biosynthesis was therefore studied in 24-hr cultures in vitro at 37 degrees of peritoneal macrophages, splenocytes, thymocytes, bone marrow, and lymph node cells. AKR mice of 2, 6, and 8 to 12 months of age were studied. Prostaglandin E1, prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha, and thromboxane B2 were measured. In cultures of peritoneal macrophages and cells from spleen, thymus, and lymph nodes, the biosynthesis of all five prostaglandin moieties was higher in those cultures prepared from 8- to 12-month-old spontaneously leukemic mice in comparison with those from 2-month-old nonleukemic AKR mice. However, when leukemia was transplanted in 3-month-old AKR mice, synthesis of all five compounds was reduced significantly in cultures of peritoneal macrophages and splenocytes prepared from these 3-month-old leukemic mice. The present data demonstrate abnormalities in prostaglandin synthesis by various cells of the immune system in leukemic mice. However, the nature of these changes was different in cultures of cells from spontaneously leukemic mice from those with transplanted leukemia. Age-related increases in prostaglandin synthesis by various lymphoid cells from spontaneously leukemic AKR mice (8 to 12 months old) occurred at a much earlier age than in BALB/c mice and may be related to the leukemic condition.
Animals↗
Bone-marrow transplantation for acute lymphoblastic leukaemia.
106 patients with acute lymphoblastic leukaemia (ALL) who received bone-marrow transplants from HLA-identical siblings during first or second remission had an actuarial survival rate at 4 years of 43 +/- 12% and an actuarial relapse rate of 32 +/- 12%. 98 patients with more advanced disease had a significantly lower probability of survival (15 +/- 9%) and a significantly higher probability of relapse (67 +/- 14%). Among high-risk patients, those transplanted in first remission had a higher survival probability (55 +/- 22%) than those transplanted in second remission (41 +/- 15%). Relapse rates in the two groups were comparable (28 +/- 24% and 31 +/- 19% respectively). Standard-risk and high-risk patients transplanted in second remission had comparable relapse rates, but there was a trend towards higher survival probability in standard-risk patients. Thus long-term disease-free survival in ALL can be achieved with bone-marrow transplantation. It is not yet certain whether transplants in first remission will result in higher survival rates than transplants in second remission; relapse rates were similar in the two groups.
Adolescent↗
Pyoderma eczema and folliculitis with defective leucocyte and lymphocyte function: a new familial immunodeficiency disease responsive to a histamine-1 antagonist.
A new familial immunodeficiency disease characterised by recurrent and persistent pyoderma, folliculitis, and atopic dermatitis is described in a father and son. It is accompanied by abnormalities of lymphocyte function (including defective proliferative responses to phytomitogens, and subnormal response in immunoglobulin production after stimulation of the lymphocytes by pokeweed mitogen) and defective leucocyte chemiluminescence responses, which were associated with defective ability for intracellular killing of microbial organisms. The abnormalities of lymphocyte and leucocyte function, as well as the clinical manifestations, responded dramatically to treatment with the histamine-1 antagonist, chlorpheniramine, suggesting that the underlying defect in this disease may relate to defective histamine metabolism or abnormal expression of histamine receptors on lymphocytes and leucocytes.
Blepharitis↗
Radioimmunoassays for the thymic hormone serum thymic factor (FTS).
Four radioimmunoassays (RIA) are described for the quantitation of serum thymic factor (facteur thymique serique, FTS), a thymic peptide hormone. Each assay employs an antibody specific for FTS, synthetic FTS (Glp-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn) as the hormone standard, and a radioiodinated FTS analogue as the tracer. Since FTS lacks a tyrosine residue, 2 FTS analogues were synthesized by the solid-phase method with tyrosyl-alanyl or 3-(2,6-dichlorobenzyl)tyrosyl-alanyl in place of the amino-terminal pyroglutamyl residue (Glp). They showed full FTS immunoreactivity and their radioiodinated derivatives served as FTS tracers. Two assays used the antiserum from a rabbit immunized with an FTS-protein conjugate. Two other assays used a monoclonal antibody against FTS produced by a hybridoma derived from mouse myeloma cells and splenocytes from a BALB/c mouse immunized with an FTS-mouse IgG conjugate (Ohga et al., 1982). All 4 RIAs were specific for FTS. The more sensitive rabbit antiserum can detect as little as 1 pg of FTS in a 50 microliters sample, which may allow quantitation of the FTS circulating in human peripheral blood.
Amino Acid Sequence↗
Age-related changes in lymphoid tissue content of prostaglandins in (NZB X NZW)F1 and CBA/H mice.
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Aging↗
Studies of immune responses in mice prone to autoimmune disorders. I. Heterogeneity of the affinities of antihapten antibodies produced by NZB, NZW, and related strains of mice.
Mice of the NZB and NZW strains and their F1 hybrid produce antihapten plaque-forming cell (PFC) responses to T-dependent antigens (trinitrophenylated bovine gamma globulin and dansylated keyhole limpet hemocyanin) which are of unusually restricted heterogeneity of affinity, are relatively lacking in low-affinity PFC, and are of relatively high average affinity. Since some low-affinity PFC are present in NZB mice early after immunization, the results suggest a particularly marked down-regulation of low-affinity antibody production by these strains. The non-autoimmune-prone F1 hybrid (NZB X CBA) produces a typical heterogeneous response containing a high proportion of low-affinity PFC. Thus, the tendency to down-regulate low-affinity PFC is not inherited as a simple Mendelian dominant trait. The response of NZB mice to T-independent antigens does not show the same restricted heterogeneity of affinity. In fact, late after injections of trinitrophenylated Ficoll, NZB mice tend to have more heterogeneous responses than nonautoimmune-prone BALB/c mice in which a marked down-regulation of high-affinity antibody-producing PFC is seen. The possible relationship between these unusual features of the immune response of NZB and some related strains and their tendency to develop autoimmune disease is discussed.
Animals↗
Bone marrow transplantation--an expanding approach to treatment of many diseases.
Thus, we can conclude that marrow transplantation has already influenced medical practice greatly. It has offered a treatment which often cures patients of more than 20 otherwise lethal diseases. The treatment so horrendously difficult and dangerous at first has already been greatly improved, simplified, and made much safer. The availability of a suitable donor has been much extended and real progress has been made in prevention and perhaps even in treatment of graft-versus-host disease. This has made possible the option of marrow transplantation for every patient in whom we think the treatment may be beneficial. The problem underlying many cases of interstitial pneumonia has been identified and patients are already benefitting clinically from this progress. Progress has also been made which promises antiviral therapy which could reduce, prevent, and ultimately eliminate the intercurrent virus infections which limit the applicability of marrow transplantation, especially for children with severe immunodeficiencies. I do not know how far this line of investigation can be taken. However, just as we have learned stepwise to use marrow transplants from matched siblings to treat many diseases, to use fetal liver in place of bone marrow, to employ matched relative donors when a matched sibling is not available, and, finally, even to use parental donors to achieve correction of SCID, we now have good reason to believe that, ultimately, we can use marrow transplantation without fear of GVHD to address many additional genetically determined and acquired diseases; certainly, for those diseases that involve any of the cells that are derived from bone marrow cells, and perhaps for those attributable even to cells of other organs and tissues, the functions of which are, in whole or in part, a consequence of interactions of marrow-derived cells and cells of ectodermal or endodermal origin, marrow transplantation may be useful. To us, the future of marrow transplantation as a major modality of treatment or prevention of many diseases, including hemoglobinopathesis, immunodeficiencies, hematologic abnormalities, abnormalities of function of marrow-derived cells, and even inborn errors of function of cells of organs and tissues not of marrow origin, seems bright, indeed. Further, with the capacity to introduce resistance genes against viruses and malignancies, autoimmune diseases, and diseases dependent on anomalies of immune response genes, marrow transplantation for many other diseases seems a more remote possibility.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenosine Deaminase↗
Persistent cytomegalovirus infection: association with profound immunodeficiency and treatment with interferon.
Cytomegalovirus (CMV) was repeatedly isolated from urine and saliva of a 20-month-old male child with recurrent episodes of pneumonia, high fever, rash, lymphadenopathy, oral ulceration, and neutropenia. Immunologic evaluation revealed decreased serum IgG and IgA, increased IgM, depressed T- and B-lymphocyte functions, and decreased natural killer (NK) activity for herpes simplex-type I virus-infected targets. NK activity was augmented following exposure of the patient's lymphocytes to interferon (IF) in vitro. The child was treated with interferon (four courses, dosage varying from 2 million U/day to 1 million U three times/week for periods of 10, 28, 80, and 67 days, respectively, interspersed over 9 months) and hyperimmune plasma infusions every 3 weeks. Toward the end of interferon therapy oral Levamisole was started and a feeding gastrostomy was inserted to provide nutritional support. Clinical recovery was associated with reversal of immunologic abnormalities except for the hypogammaglobulinemia. Aggressive antiviral therapy (e.g., with IF) followed by immunostimulation (e.g., with Levamisole) may prove effective in controlling certain viral infections in immunodeficiency disorders.
Agammaglobulinemia↗
Adenosine 5'-triphosphate (ATP)-mediated stimulation and suppression of DNA synthesis in lymphoid cells. II. Suppressive effect of ATP on murine T-cell functions.
The suppressive effects of ATP on murine T-cell functions were studied. The suppressive effects of ATP as well as adenosine on the DNA synthesis of spleen cells are due to the presence of mature T-cells, because ATP has no suppressive effect on athymic nu/nu spleen cells. Further characterization of the cells which are responsible for ATP-mediated suppression of DNA synthesis revealed that the cells are nylon wool-adherent T-cells and PHA-reactive T-cells. In addition, the suppressive effects of ATP on both spontaneous and mitogen-induced proliferative responses are stronger than that of adenosine, and T-cells are more sensitive to ATP than B-cells. The observation that both ATP and adenosine have unique effects on T-cells compared to B-cells may contribute toward explaining why patients with severe combined immunodeficiency (SCID) associated with adenosine deaminase (ADA) deficiency have greater T-cell than B-cell abnormalities.
Adenosine↗
Cycling of peripheral blood and marrow lymphocytes in cyclic neutropenia.
A 16-month-old male patient with cyclic neutropenia was found to have cyclic fluctuations of monocytes, lymphocytes, platelets, and eosinophils in the peripheral blood. Changes in lymphocyte counts were not obviously related to B, T, or natural killer cells. All classes of immunoglobulins were elevated throughout the cycle. Studies of the marrow morphology revealed remarkable cyclic oscillations of lymphoid as well as myeloid lineage cells. Granulocyte-macrophage progenitors (CFU-c) cycled and were virtually absent 1 wk prior to the neutropenic nadir. The cyclic changes in marrow lymphoid cell numbers were primarily due to changes in numbers of surface immunoglobulin negative (sIg-), cytoplasmic Ig+ (cIg+) pre-B cells. Pre-B cell numbers cycled from normal to extraordinarily elevated values with the same periodicity but reciprocal to the neutrophil cycle. We propose that the primary defect in cyclic neutropenia may either be a periodic failure of an early myeloid differentiation factor or a blunted response of early myeloid precursors to a common hemopoietic growth factor. This may lead to periodic fluctuations in the production or delivery of growth factors (or factor) that influence early stages of differentiation of other hemopoietic cells, including pre-B cells. The essential periodic deficiency is consequently reflected in deficient production of CFU-c accompanied by excessive production or accumulation of pre-B cells (and probably other hemopoietic precursors) in the marrow.
Adult↗
Changes in surface antigens of immature thymocytes under the influence of T-cell growth factor and thymic factors.
Peanut agglutinin-positive thymocytes, peanut agglutinin-negative thymocytes, cortisone-resistant thymocytes, and unfractionated thymocytes were prepared from congeneic C57BL/6 Tla mice. By using surface iodination and immunoprecipitation of solubilized antigen with specific antisera (e.g., anti-H-2D, anti-TL, anti-Qa2/3, and anti-gp70), the released specific antigens were electrophoresed on polyacrylamide gels, and their radioactivity was measured. The relative percentages of surface antigens H-2D, TL, Qa2/3, and gp70 were 3.2%, 47.5%, 2.5%, and 46.8%, respectively, for peanut agglutinin-positive thymocytes; 31.8%, 4.4%, 32.7%, and 31.1%, respectively, for cortisone-resistant thymocytes; 13.2%, 28.7%, 12.3%, and 45.8%, respectively, for peanut agglutinin-negative thymocytes; and 7.7%, 27.1%, 4.3%, and 60.9%, respectively, for unfractionated thymocytes. After incubation with thymosin fraction V or T-cell growth factor (interleukin II) for 20 hr, the changes in surface antigens of peanut agglutinin-positive thymocytes closely correlated with their normal maturation (i.e., H-2D increases and TL decreases). Thymic factors (e.g., thymosin alpha 1, thymopoietin pentapeptide, facteur thymic serique) had only small or no effects on surface antigens of peanut agglutinin-positive thymocytes. The results suggest that peptides yet to be identified in thymosin fraction V may play an important role in intrathymic evolution and that T-cell growth factor is possibly a peripheral signal derived from activated T cells that modulates T-cell receptors and may be a critical regulator of intrathymic cellular development.
Animals↗
Influence of diet on vascular lesions in autoimmune-prone B/W mice.
Autoimmune-prone B/W mice, which are known to develop severe glomerulonephritis and vasculitis, also are found to develop arteritis and proliferative and fatty-proliferative lesions of the aorta and its branches as well as renal inflammatory lesions. High intake of saturated fat in the diet enhances the development of these atherosclerotic and autoimmune lesions significantly in female mice, whereas restriction of dietary calories and fat inhibits their development. Ad lib feeding of laboratory chow, high in fiber and low in fat, does not foster development of vascular lesions but does permit the development of autoimmune renal disease.
Animals↗