Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.
The sensitivity of eggs of Echinococcus multilocularis to environmental and controlled laboratory conditions was tested. Egg material was exposed and the infectivity was subsequently monitored by in vitro activation and by oral infection of the natural host, Microtus arvalis. To study the impact of environmental conditions in an endemic area of south-western Germany, eggs were sealed into bags of nylon mesh and exposed to the natural climate during various seasons. The maximal survival time of eggs was 240 days in an experiment performed in autumn and winter and 78 days in summer. A study of the tenacity of eggs under laboratory conditions revealed a high sensitivity to elevated temperatures and to desiccation. At 45 degrees C and 85-95% relative humidity the infectivity was lost after 3 h as well as after 4 h exposure to 43 degrees C suspended in water. Exposure to 27% relative humidity at 25 degrees C as well as exposure to 15% relative humidity at 43 degrees C resulted in a total loss of infectivity within 48 and 2 h, respectively. Temperatures of 4 degrees C and of -18 degrees C were well tolerated (478 days and 240 days survival, respectively), whereas exposure to -83 degrees C and to -196 degrees C quickly killed off the eggs (within 48 h and 20 h, respectively). Eggs of E. multilocularis were not killed off by exposure to various commercially available disinfectants applied according to the manufacturers' instructions and by exposure for 24 h to low concentrations of ethanol. Irradiation with 40 krad. from a 137Caesium source prevented the development of metacestodes but allowed seroconversion of infected rodents.
The T-cell antigen receptor (TCR) consists of heterodimeric glycoproteins (TCR a,4 or yS) that demonstrate homology with immunoglobulins. Noncovalently associated with the afi (or y8) heterodimer are at least five nonvariant proteins (CD3-y, -8, -e, -j, and -ig), which together comprise the TCR-CD3 complex. The stoichiometry of the antigen receptor has been assumed to be either apyBvSiCor a(y8e{7g.In this paper we provide several lines of evidence that support the notion that the mature TCR-CD3 complex on the cell surface contains two CD3-E polypeptide chains. Transfection of two murine T cell-T cell hybridomas with the human DNA encoding CD3-e protein demonstrated that both murine and human CD3-e chains were present within the same TCR-CD3 complex. Analysis of thymocytes isolated from transgenic mice that expressed high copy numbers of the human CD3-e gene showed that the heterologous human CD3-e subunits were coexpressed with murine CD3-E in the same TCR-CD3 complex. Since CD3-e was shown to form disulfide-linked homodimers both in human and murine T cells, the two CD3-e subunits present in the TCR-CD3 complex were in direct contact with one another. The presence of two CD3-E polypeptide chains in close proximity to one another in the TCR-CD3 complex may have important implications for its assembly and its signal transduction mechanisms.The T-cell antigen receptor (TCR) on thymus-derived lymphocytes (T cells), which recognizes antigen in association with either class I or class II major histocompatibility complex (MHC) products, consists of a heterodimer of glycoproteins, the a and /3 chain (1). A second form of the TCR, the y3 receptor, also exists on a smaller fraction of peripheral T cells (2). The TCR heterodimers are noncovalently associated with at least five nonvariant polypeptides: CD3-y, -8, -E, -;, and -'r (3, 4). CD3-; exists either as a disulfide-linked homodimer or, in the minority of TCR-CD3 complexes, as a disulfide-linked heterodimer with the CD3-i1 chain (4). The CD3 proteins appear to play an important role in transport of the TCR heterodimer to the cell surface and signal transduction after the TCR binds its appropriate ligand. The specific number of polypeptide chains that compose the TCR-CD3 complex on the cell surface has not been precisely determined. The stoichiometry has generally been assumed to be either a/3y6e4 or a/3^y&e'>r (3,4). In this paper, we analyze the stoichiometry of CD3-E in the complex by expression of human CD3-e (CD3-eh) in murine T cells. We provide evidence that there are two CD3-E polypeptide chains in close proximity to one another within the mature TCR-CD3 complex expressed on the cell surface.
We recently established that molecular chimeras of major histocompatibility complex (MHC) class II molecules, created via retroviral transfer of allogeneic class II cDNAs into bone marrow cells (BMCs), alleviated complications associated with mixed BMC chimeras while leading to T cell tolerance to renal grafts sharing the transferred class II. Initially demonstrated for allogeneic transplants in miniature swine, this concept was extended to T-dependent antibody (Ab) responses to xenogeneic antigens (Ags) in the pig --> baboon combination. Successful down-regulation of T cell responses appeared, however, to be contingent on a tight lineage-specific expression of transferred class II molecules. The present studies were, therefore, designed to evaluate the influence of construct design and cellular environment on expression of retrovirally transferred xenogeneic class II cDNAs. Proviral genomes for pig class II SLA-DR expression, differing only at the marker neo(r) or enhanced green fluorescent protein (EGFP) gene, showed increased membrane SLA-DR density on HLA-DR(-) fibroblasts as well as HLA-DR(+), TF-1 erythroleukemia cells. More importantly, HLA-DR(+) human B cell lines, although efficiently transduced with pig DR retroviruses, exhibited unstable surface pig DR. Surface pig DR- B cells, nevertheless, stimulated autologous human T cells pre-sensitized to pig Ags, a proliferation likely occurring through presentation of class II-derived peptides. Collectively, these data suggest that surface expression of transferred class II molecules is not related to the ability of recipient cells to synthesize xenogeneic class II molecules but rather to their Ag processing capacities.
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