Biomedical subjects
E Engleman
Publications and source records attributed to E Engleman.
T-cell receptor-negative natural killer cells display antigen-specific cytotoxicity for microvascular endothelial cells.
Based upon prior demonstrations that human microvascular endothelial cells (ECs) could serve as natural killer (NK) cell targets, we established NK cell lines and clones by repeated stimulation of highly purified CD16-positive, CD3/T-cell receptor (Ti)-negative cells with allogeneic ECs. After 3 weeks in culture these lymphoid cells, which neither expressed surface CD3/Ti molecules nor rearranged Ti beta- or gamma-chain genes and which lysed K562 human erythroleukemia cells, displayed specific cytotoxicity for the stimulating ECs. Furthermore, freshly isolated NK cells bound and then removed from each of several allogeneic EC lines displayed selective cytotoxicity for the adsorbing EC line. These results provide evidence for alloantigen-specific recognition of microvascular ECs by NK cells that appears to be determined, at least in part, at the level of adherence. We discuss the implications of these findings with respect to the rejection of vascularized organ allografts.
Peptides derived from the CDR3-homologous domain of the CD4 molecule are specific inhibitors of HIV-1 and SIV infection, virus-induced cell fusion, and postinfection viral transmission in vitro. Implications for the design of small peptide anti-HIV therapeutic agents.
Peptides 12-25 amino acids in length from the V1J1 region of the CD4 molecule (residues 1-120) were synthesized as randomly derivatized, deliberately derivatized, or pure peptide products, and tested for their ability to inhibit HIV-1-induced cell fusion, HIV-1 and SIV infection of CD4-positive human cells, HIV-1 envelope glycoprotein binding to the CD4 molecule, CD4-neutralizing antibody binding to the CD4 holoreceptor, and CD4-dependent cellular immune function in the mixed lymphocyte and cytotoxic T-cell bioassays. Only peptides derived from the complementarity-determining region 3 (CDR3)-homologous domain of CD4, in particular CD4(81-92) and CD4(81-101), were effective antiviral agents. Within the CD4(81-92) series, R-group derivatization of selective amino acid residues was an absolute requirement for biological activity. The prototype compound T1C4E5-tribenzyl-K10-acetyl-TYICEVEDQKEE inhibited HIV-1-induced cell fusion at 32 microM, HIV-1 infection of CEM-SS cells at 10 microM, SIV infection of CEM-174 cells at less than 125 microM, gp120/CD4 binding at 60 microM, and postinfection cell-mediated viral transmission at 10-15 microM. Compounds of identical structure and derivatization, but of altered primary sequence, were substantially less active, or without activity, in these assays. These data indicate that the effect of amino acid derivatization of the CD4(81-92) peptide was most likely restriction of the flexible underivatized peptide backbone to a conformation closely approximating that of the CDR3-homologous gp120 binding site of the native CD4 molecule. Peptide antiviral activity was specific, as judged by lack of cytotoxicity, lack of inhibition of HTLV-1-induced cell fusion, and lack of inhibition of CD4-dependent cellular immune function in vitro. Further derivatization of the prototype compound involving the production of cyclic congeners yielded peptides with submicromolar potency to block HIV-1 infection, strengthening the hypothesis that previous peptide derivations accomplished partial restriction of the conformation of CD4(81-92) to one favorable for interaction with gp120. Concentrations of the original prototype compound T1C4E5-tribenzyl-CD4(81-92) that inhibited infection in vitro more than 50% could be achieved for several hours by intravenous infusion in primates and were well-tolerated at these levels. The peptide was not efficacious to inhibit establishment of viral infection at these doses; however, peptide treatment did lower average viral antigenemia and delay the cumulative time to morbidity relative to the control group.
Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation.
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Characterization and epitope mapping of a human monoclonal antibody reactive with the envelope glycoprotein of human immunodeficiency virus.
A human monoclonal antibody (IgG2, lambda), 1B8.env, was produced, reactive with the envelope glycoprotein of human immunodeficiency virus (HIV). The antibody specifically stains cells infected with HIV, as assessed by indirect immunofluorescence analysis and reacts with determinants displayed on the surface of infected cells. In Western blot analysis, the antibody reacts with bands of 160 and 41 kD, consistent with the precursor and transmembrane forms of the HIV envelope glycoprotein. The antibody also reacts specifically in immunofluorescence and Western blot analysis with cells infected with the recombinant vaccinia virus VSC-25, which contains the envelope gene of HIV. With the lambda gt11 expression vector, the epitope recognized by 1B8.env was mapped to a region of 11 amino acids in the coding region of gp41. This domain is highly conserved between several otherwise highly variable HIV isolates. In addition, this epitope appears to be recognized by the vast majority of HIV seropositive individuals. Although antibody IB8.env does not neutralize HIV virion infectivity or virally mediated cell fusion, the results presented here demonstrate the feasibility of generating and characterizing human monoclonal antibodies to HIV with these techniques. Additional antibodies produced in this manner will help to further characterize the humoral response to HIV infection, define biologically significant determinants on HIV proteins, and may be useful in clinical applications.
Antibody to human immunodeficiency virus correlates with decreased T helper lymphocytes in asymptomatic individuals.
To examine the relationship between human immunodeficiency virus (HIV) seropositivity and T lymphocyte subsets in a clinically well population, we assayed HIV antibody and analyzed T lymphocyte subsets in 30 people at increased risk for acquired immunodeficiency syndrome (AIDS) who were clinically well. Seventy-six percent of the HIV-seropositive individuals had abnormally low numbers of T helper lymphocytes, and HIV seropositivity was strongly correlated with an abnormally low number of T helper cells (p less than 0.00002). Among these clinically well subjects at increased risk for AIDS, HIV-sero-positive individuals had a significant decrease in mean T helper lymphocytes and mean T helper:T suppressor ratios as compared to those who were seronegative (483 cells/mm3 vs 915 cells/mm3, p less than 0.002; and 0.80 vs 1.7, p less than 0.002, respectively). Because of the strong correlation of HIV seropositivity and abnormally low numbers of T helper lymphocytes in this asymptomatic population, these findings suggest that asymptomatic seropositive individuals should be followed closely for development of AIDS-related disease and should be considered for future antiviral therapy when it becomes available.
Transmission of lymphadenopathy-associated virus/human T lymphotropic virus type III in sexual partners. Seropositivity does not predict infectivity in all cases.
To investigate transmission of lymphadenopathy-associated virus (LAV)/human T lymphotropic virus type III (HTLV-III) in long-term sexual partners, and the relationship between lymphadenopathy-associated virus seropositivity and transmission, nine couples (five heterosexual and four homosexual) at increased risk for acquired immune deficiency syndrome (AIDS) were studied. In two heterosexual couples, transmission of lymphadenopathy-associated virus from a seropositive man at increased risk to his monogamous wife occurred. In one couple, the wife of a man with hemophilia had lymphadenopathy-associated virus antibody and decreased T helper cells; in the other couple, the wife of a bisexual intravenous drug-user had AIDS. Neither woman had a recognized AIDS risk except marriage to a seropositive man at increased risk. However, study of the other couples revealed that regular sexual contact with seropositive persons over long periods did not always lead to evidence of lymphadenopathy-associated virus infection. This study suggests that presence of lymphadenopathy-associated virus antibody does not always indicate a high degree of infectivity.
Purified interleukin-2 induces proliferation of fresh human lymphocytes in the absence of exogenous stimuli.
Highly purified interleukin-2 (IL-2) induced proliferation of fresh human peripheral blood mononuclear leukocytes (PBML) in the absence of identifiable exogenous mitogenic or antigenic stimuli. Dose dependent proliferation was observed with three IL-2 preparations, including two preparations purified from natural sources and a preparation produced by recombinant DNA techniques. Both T and non-T cells proliferated. Purified helper/inducer and suppressor/cytotoxic T cells cultured in the absence of non-T cells proliferated only weakly; the proliferative response to IL-2 was restored by the addition of irradiated non-T cells. Proliferation to IL-2 was not blocked by the monoclonal antibody anti-Leu 4, which reacts with a component of the T-cell receptor complex for antigen and blocks mitogen and antigen-induced T-cell responses. Monoclonal antibody to HLA-DR also failed to significantly block the proliferation of resting cells to IL-2. The IL-2 induced proliferative response thus appears to be dependent on interactions between different subpopulations of PBML but probably does not simply reflect augmentation by IL-2 of antigen-driven or autoreactive processes.
Transient antibody to lymphadenopathy-associated virus/human T-lymphotropic virus type III and T-lymphocyte abnormalities in the wife of a man who developed the acquired immunodeficiency syndrome.
We present evidence of transmission of lymphadenopathy-associated virus (LAV)/human T-lymphotropic virus type III (HTLV-III) from a man to his wife, and a return to a normal number of T-helper lymphocytes and loss of antibody after discontinuing sexual exposure to LAV/HTLV-III. The man had hemophilia A, and developed the lymphadenopathy syndrome, antibody to LAV, and a low number of T-helper lymphocytes. His wife, who had no risks for the acquired immunodeficiency syndrome other than sexual contact with him, developed LAV antibody (titer, 1:160) and a mildly decreased number of T-helper cells. The husband subsequently developed the syndrome and lost the LAV antibody. During 10 months of follow-up his wife remained clinically well, discontinued exposure to semen, and then lost the LAV antibody, and regained a normal number of T-helper cells.
Significance of HLA antigens and the mixed lymphocyte reaction in psoriasis.
Human Major Histocompatibility (HLA) complex antigens B13, BW16, BW17, CW6 and D-MA are increased in frequency in patients with psoriasis. Of these, the strongest association is with HLA-CW6 and D-MA, with a relative risk of 10.4. Since no strong association with any HLA-A locus antigen is seen, it seems likely that the disease susceptibility gene for psoriasis lies close to the HLA-D locus, which is defined by the use of the mixed lymphocyte reaction (MLR). In the mouse, the Immune response (Ir) genes are found in the MLR region and it is thought that Ia antigens lie at a corresponding location in man. Recently, we have demonstrated that human epidermal cells cause stimulation in the mixed lymphocyte reaction. Lymphocyte antigens which stimulate in this reaction are known to be products of HLA genes and anti-HLA-D sera block stimulation by epidermal cells. It is possible that these antigens may be involved in the regulation of cell--cell communication. Psoriasis is a disease characterized by epidermal hyperproliferation. It is possible, therefore, that an HLA-linked deficiency of recognition between epidermal cells exists in patients with psoriasis and that this defect allows abnormal cellular proliferation to occur.