Biomedical subjects

R Geha

Publications and source records attributed to R Geha.

34 records · Page 2Linked to original sources

PubMed1989

Proliferation of highly purified T cells in response to signaling via surface receptors requires cell-cell contact.

Lymphocyte proliferation is associated with cell-cell aggregation. In order to assess the importance of cell-cell contact in T-cell proliferation we examined the effect of disruption of cellular aggregation by anti LFA-1(4) mAb on T-cell proliferation. Monocyte-dependent T-cell proliferation induced by anti-CD3 mAb, pairs of anti-CD2 mAbs, or PHA was inhibited by anti-LFA-1 mAb. Monocyte-independent proliferation of highly purified T cells to anti-CD3 mAb plus PMA or plus IL-2 and to PHA plus IL-2 was, surprisingly, also inhibited by anti-LFA-1 mAb. Anti-LFA-1 mAb caused the partial inhibition of both low-affinity and high-affinity IL-2 receptor and the complete inhibition of IL-2 synthesis. In contrast to the above, the proliferation of highly purified T cells to PMA plus ionomycin was not inhibited by anti-LFA-1 mAb. These results suggest that optimal activation of highly purified T cells via cell surface receptors requires LFA-1-dependent cell-to-cell contact between proliferating T cells as well as between T cells and accessory cells. Such contact appears to be crucial for initiating IL-2 production and for optimal action of IL-2 through its receptor.

Adult↗

PubMed1989

Recombinant interleukin 2 therapy in severe combined immunodeficiency disease.

Severe combined immunodeficiency disease (SCID) is a congenital disorder of severe B- and T-lymphocyte dysfunction in which several pathogenic mechanisms have been identified. The present study describes a female child with SCID who had a primary defect in the ability of T cells to secrete interleukin 2 (IL-2). B- and T-cell numbers were normal, but their functions were severely deficient. Mitogen and antigen-driven lymphoproliferative responses were diminished but were correctable in vitro with recombinant IL-2 (rIL-2). The patient's phytohemagglutinin-stimulated lymphocytes expressed IL-2 receptors normally. Despite the presence of the gene for IL-2, the patient's cells were grossly deficient in messenger RNA for IL-2 and endogenous IL-2 production. Pokeweed mitogen-driven B-cell differentiation was decreased and was not corrected by the addition of normal T cells to the B cells. Two attempts at immune reconstitution by haploidentical bone marrow transplantation failed. Therapy with rIL-2 (30,000 units/kg, given daily i.v.) resulted in marked clinical improvement as well in improved T-cell functions. The child, now 3 yr old, has been on rIL-2 therapy for 2 yr and receives rIL-2 (30,000 units/kg) three times weekly at home. This case study points to a new direction in the treatment of such disorders with rIL-2.

B-Lymphocytes↗

PubMed1989

Blocking of passive sensitization of human mast cells and basophil granulocytes with IgE antibodies by a recombinant human epsilon-chain fragment of 76 amino acids.

The recombinant peptide corresponding to residues 301-376 at the junction of constant regions 2 and 3 of the human IgE epsilon chain blocked the in vivo passive sensitization of human skin mast cells and in vitro sensitization of human basophil granulocytes with human IgE antibodies. An injection of the recombinant peptide or E myeloma protein into normal skin sites 1 hr before sensitization with an allergic serum blocked passive sensitization. In this system, approximately 10-fold higher molar concentration of the recombinant peptide than E myeloma protein was required for 50% inhibition of Prausnitz-Küstner reactions. When the mononuclear cells of two normal individuals were preincubated with the recombinant peptide or E myeloma protein for 15 min before passive sensitization with the same allergic serum and the cells were challenged with an optimal concentration of an antigen, approximately 11- to 13-fold higher concentration of the recombinant peptide than E myeloma protein was required for 50% inhibition of antigen-induced histamine release. Further studies with several recombinant peptides indicated that amino acid resides 363-376 in the Fc epsilon-chain fragment are not essential for binding of the peptide to Fc epsilon-chain receptor I.

Base Sequence↗

PubMed1988

The mast cell binding site on human immunoglobulin E.

Antibodies of the immunoglobulin E isotype sensitize mast cells and basophils for antigen-induced mediator release by binding through the Fc portion to a high-affinity receptor (Fc epsilon R1, Ka = 10(9)M-1) on the cell surface causing the clinical manifestations of type I hypersensitivity. As the amino acid sequence of the human epsilon chain is now known, attempts have been made to map the Fc epsilon R1 binding site on IgE to a fragment smaller than Fc epsilon using proteolytic cleavage products, none of which proved to be active. Cleavage between the C epsilon 2 and C epsilon 3 domains released two inactive fragments, suggesting that the junction between these segments could be important in receptor binding. This region is protected against protease digestion in the rat IgE complex with the receptor of rat basophilic leukaemia cells. Here we report the mapping of the mast cell receptor binding site on human IgE to a sequence of 76 amino acids at the C epsilon 2/C epsilon 3 junction. Recombinant peptides containing this sequence inhibit passive sensitization of skin mast cells in vivo and sensitize mast cells to degranulation by anti-IgE in vitro almost as efficiently as a myeloma IgE. Fragments containing the separate domains are inactive. Additional sequences are required for rapid assembly of fragments into disulphide-linked dimers, suggesting that a single chain can form the active site. In a three-dimensional model of the human Fc epsilon, the two identical segments are far apart. Each folds to generate a cleft between the C epsilon 2 and C epsilon 3 domains on the surface of the Fc epsilon. The docking of IgE on to mast cells could take place within this cleft.

Amino Acid Sequence↗

PubMed1986

Altered immunoglobulin status in congenital nephrotic syndrome.

The serum and urine immunoglobulin concentrations of a patient with congenital nephrotic syndrome of the Finnish type (CNS) were studied during an 11 month period. The serum IgG levels were never higher than 25% and most were below 2% of normal infant values. Serum IgM levels rose to three times normal and IgA concentrations varied. The selective protein index (SPI) showed apparent selective proteinuria (SPI less than 0.06). Intravenous gamma-globulin infusions were carried out to raise serum IgG levels. The infused IgG was initially contained within the intravascular space, but within 30 hours 55% was lost in the urine. Compared to the steady state, the renal clearance of IgG showed a 20-fold increase immediately post-infusion. We conclude that children with CNS should be considered essentially agammaglobulinemic throughout the first year of life and perhaps longer. Intravenous IgG infusions provide only hours of sufficient IgG replacement due to rapid urinary losses and may be detrimental.

Agammaglobulinemia↗

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↗

PubMed1982

Reconstitution after transplantation with T-lymphocyte-depleted HLA haplotype-mismatched bone marrow for severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is potentially correctable by bone marrow transplantation if a patient has a suitable histocompatible donor. In the absence of an HLA-matched donor, lethal graft-versus-host disease (GVHD), which is mediated by alloreactive donor T cells, may occur. In an attempt to prevent GVHD in one SCID patient lacking a matched donor, we treated maternal haplomismatched bone marrow with a unique nonmitogenic T-cell-specific monoclonal antibody (anti-T12) and complement to remove mature T cells. Despite the removal of greater than 99% mature T cells, the child developed significant life-threatening GVHD, which was terminated by a 5-day course of intravenous anti-T12. Subsequently, immune reconstitution occurred by 6 wk: the mature circulating T cells proliferated in response to soluble and allo-antigens in vitro and provided help for B-cell immunoglobulin synthesis. The patient was removed from a protective environment and discharged without evidence of further infection. Both HLA and chromosomal analyses showed that the circulating cells in the patient were of maternal origin. More importantly, the maternal T cells were no longer reactive with recipient cells. Mixing experiments indicated that the state of tolerance that resulted in this chimera was not due to active suppression. We conclude that HLA-mismatched transplantation for SCID can be undertaken if mature alloreactive donor T lymphocytes are depleted before and after bone marrow grafting.

Antibodies, Monoclonal↗

PubMed1981

Immunodeficiency associated with loss of T4+ inducer T-cell function.

We investigated the immune function of a patient with anergy and acquired hypogammaglobulinemia. Despite normal numbers of B cells and T4+ inducer and T5+ suppressor T cells, this patient's lymphocytes did not produce immunoglobulin, proliferate in response to soluble antigens, or generate helper factors in vitro. In addition, her T4+ T cells did not express la molecules after stimulation by soluble antigen. In mixing experiments, her T cells did not induce immunoglobulin secretion by B cells from a normal, HLA-D-identical sibling; this failure was not due to excessive suppression, since the patient's T cells did not abrogate immunoglobulin production by the normal sibling's T and B cells. Moreover, the patient's B cells secreted immunoglobulin in the presence of the sibling's T4+ cells. In contrast to the deficient inducer cells, the patient's T5+ T cells were capable of expressing suppressor-cell functions. These results indicate that immunodeficiency may occur because of a selective loss of T4+ inducer function.

Agammaglobulinemia↗

PubMed1980

Hypogammaglobulinemia in patients with cystic fibrosis.

To investigate some aspects of immune function in cystic fibrosis, we measured serum immunoglobulins in 419 patients. Twenty-two per cent of the 154 patients less than 10 years old had hypogammaglobulinemia-G, whereas the older patients had normal or elevated serum immunoglobulins. A single mechanism accounting for the extraordinary prevalence of hypogammaglobulinemia in young patients with cystic fibrosis was not defined in studies of T and B-lymphocyte function in vitro or in studies of IgG metabolism in vivo. Analysis of objective clinical data, including arterial blood gases, chest roentgenograms, and bacteriologic cultures, indicated that the patients with hypogammaglobulinemia had significantly less severe lung disease than did age-matched patients with cystic fibrosis and normal or elevated IgG levels. We conclude that progression of lung disease may be due in part to a hyper-immune response.

Adolescent↗

PubMed1978

Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marrow transplantation.

Two patients with the Wiskott-Aldrich syndrome had complete donor lymphoid and hematopoietic engraftment after successful allogeneic bone-marrow transplantation. One patient had had only a temporary donor T-lymphocyte graft after a previous transplantation, for which he had been prepared with cytarabine and cyclophosphamide; the patient's own T lymphocytes returned six months later. A repeat transplant, for which the patient was prepared with anti-human thymocyte serum, total-body irradiation and procarbazine, resulted in complete donor engraftment. The second patient underwent a successful transplantation after similar preparation, except that procarbazine was omitted. At 11 and five months after transplantation both had normal hematopoiesis and no evidence of graft-versus-host disease. This treatment of the Wiskott-Aldrich syndrome may be a model for the correction of other genetically determined immune and hematologic bone-marrow disorders.

Antilymphocyte Serum↗

PubMed1976