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Biomedical subjects

N L Letvin

Publications and source records attributed to N L Letvin.

At least 217 records · Page 12Linked to original sources
PubMed1987

Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Apposition of degenerative Langerhans cells and cytotoxic lymphocytes during the development of acquired immunodeficiency syndrome.

A T-cell tropic retrovirus, simian immunodeficiency virus (SIV), has recently been isolated from immunodeficient rhesus monkeys. This virus has remarkable similarities to human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome. Subsequent studies of simian infection with SIV have shown it to be a relevant animal model for studying the pathogenesis of AIDS in man. In both HIV-infected humans and SIV-infected monkeys, a cutaneous maculopapular eruption has been described. To date, the pathogenesis and possible relationship of these exanthema to the evolution of systemic immunosuppression have remained obscure. In this study, the mononuclear cell infiltrates that characterize skin rashes of SIV-infected rhesus monkeys were found to be composed predominantly of cells with phenotypic characteristics of cytotoxic/suppressor (T8+) lymphocytes and natural killer cells. Many of these cells expressed membrane-bound interleukin-2 receptor molecules. Double labeling and immunoelectron microscopy revealed these cells in direct contact with degenerative Langerhans cells within the epidermis and dermis. These observations suggest that the cutaneous rash associated with SIV infection may be the consequence of target cell injury of Langerhans cells by effector cells with cytotoxic potential.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Lymphadenopathy in macaques experimentally infected with the simian immunodeficiency virus (SIV).

A T-cell tropic lentivirus of macaques the simian immunodeficiency virus (SIV), has morphologic, growth, and antigenic properties that indicate that it is related to the human immunodeficiency virus (HIV), the etiologic agent of the acquired immune deficiency syndrome (AIDS) in humans. Six juvenile macaques developed persistent lymphadenopathy (greater than 3 months in duration) after inoculation with SIV. The histologic appearance of the lymph nodes was characterized by marked follicular hyperplasia with abundant proliferative B cells infiltrating into the paracortex. The number of T8-positive lymphocytes equaled or exceeded the number of T4-positive lymphocytes in the paracortex. These findings, in association with immunologic abnormalities and a previously observed fatal immunodeficiency syndrome in SIV-infected macaques, provide further evidence of the importance of SIV-induced disease in macaques as a model for the study of AIDS.

AIDS-Related Complex↗
PubMed1987

Simian models for AIDS.

The macaque immunodeficiency syndrome has many parallels to AIDS in humans. Affected monkeys develop profound, prolonged T lymphocyte dysfunction and die of lymphomas or opportunistic infections. We recently isolated a virus that we call SIV from four sick macaque monkeys. The morphology, growth characteristics, and antigenic properties of this virus indicate that it is related to the causative agent of human AIDS. The pathogenicity of this newly isolated virus was tested in macaque monkeys. Five of six died between 127 and 352 days following inoculation. The animals developed a wasting syndrome and died with adenovirus pancreatitis and/or pneumonia and primary retroviral encephalitis. Immunological abnormalities in these animals included a decrease in circulating T4+ lymphocytes and depressed peripheral blood lymphocyte proliferative response to pokeweed mitogen. The SIV monkey model holds great promise for testing antiviral agents and for the development of vaccines against AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1986

The role of the 2H4 molecule in the generation of suppressor function in Con A-activated T cells.

The molecular basis for the suppression generated in a concanavalin A (Con A)-activated T cell culture remains unknown. In this study, we have attempted to determine whether the 2H4 and 4B4 molecules on Con A-activated T cells play some role in the generation of suppression by such cells. We have shown that Con A-activated suppressor cells belong to the 2H4+ subset of T cells but not the 4B4+ (2H4-) subset. Con A-activated T cells exerted their optimal suppressor function on day 2 in culture, a time at which the expression of 2H4 on such cells was maximal and 4B4 was minimal. Furthermore, the stimulation of T cells with the higher concentration of Con A generated the stronger suppressor function. At the same time, both 2H4 expression and density were increased and 4B4 expression and density were decreased on such Con A-activated T cells. More importantly, the treatment of Con A-activated T cells with anti-2H4 antibody but not with anti-4B4, anti-TQ1, or anti-T4 antibodies can block the suppressor function of such cells. Taken together, the above results strongly suggest that the 2H4 molecule itself may be involved in the generation of suppressor function in Con A-activated T cells. The 2H4 antigen on such cells was shown to be comprised of 220,000 and 200,000 m.w. glycoproteins. Thus this study indicates that the 220,000 and 200,000 m.w. structure of the 2H4 molecule may itself play a crucial role in the generation of suppressor signals of Con A-activated cells.

Antibodies, Monoclonal↗
PubMed1986

Herpesvirus saimiri strain 11 immortalizes a restricted marmoset T8 lymphocyte subpopulation in vitro.

Herpesvirus saimiri induces a fatal lymphoproliferative syndrome in a variety of New World primate species. We now show that cell lines derived from PBL of the common marmoset by in vitro-immortalization with H. saimiri strain 11 represent a remarkably restricted lymphocyte population. These cell lines have NK cell function, phenotypically express both suppressor/cytotoxic (T8) and NK cell (NKH1)-associated antigens, and express a T cell receptor. This subpopulation of lymphocytes is a very minor population of cells in the peripheral blood of common marmosets (less than or equal to 3%). The specificity in the interaction between H. saimiri strain 11 and a subpopulation of common marmoset lymphocytes represents an example of a restricted viral lymphotropism and may have important implications for the disease induced by this virus in New World monkeys.

Animals↗
PubMed1986

The cellular basis for the induction of antigen-specific T8 suppressor cells.

The cellular basis for the generation of antigen-specific T8 suppressor cells with high doses of antigen has been studied. We separated the T4 subset of human T cells into T4+2H4+ and T4+2H4- subpopulations with a recently developed monoclonal anti-2H4 antibody. T8 cells could be consistently activated to suppress a primary anti-2,4-dinitrophenyl (DNP) antibody response in vitro with unfractionated T4 cells or with the T4+2H4+ subset but not the T4+2H4- subset. In contrast, the T4+2H4- subset functioned as the helper inducer for the anti-DNP antibody response. With keyhole limpet hemocyanin (KLH)-stimulated T4+2H4+ cells we could efficiently induce antigen-specific suppressor activity of fresh T8 cells. In contrast, the T4+2H4+ subset could not effect suppression in the absence of T8 cells. Our findings indicate that the T4+2H4+ subset of human T cells is the suppressor inducer of specific T8 cells in an antigen-specific DNP-KLH system.

Antibodies, Monoclonal↗
PubMed1986

Nononcogenic deletion mutants of herpesvirus saimiri are defective for in vitro immortalization.

Herpesvirus saimiri L-DNA sequences between 0.0 and 4.0 map units (4.5 kilobase pairs) are required for oncogenicity; these sequences are not required for replication of the virus. To investigate the basis for the lack of oncogenicity of mutants with deletions in this region and to study the function of this region, we developed a reliable system for in vitro immortalization by herpesvirus saimiri. In contrast to peripheral blood lymphocytes from cotton-top tamarins (Saguinus oedipus) and owl monkeys (Aotus sp.), infection of peripheral blood lymphocytes from common marmosets (Callithrix jacchus) in vitro with herpesvirus saimiri consistently yielded continuously growing lymphoblastoid cell lines. Such cell lines were established using strains of herpesvirus saimiri from group A and group non-A, non-B; however, repeated attempts to immortalize common marmoset peripheral blood lymphocytes using strains from group B were not successful. Common marmoset cell lines immortalized by herpesvirus saimiri were T12+, T8+, T4-, and B1-, indicating that they were derived from suppressor/cytotoxic T lymphocytes. Cell lines could not be established using the nononcogenic mutants 11att and S4, both of which were derived from the group A strain 11 virus. Strain 11att has a spontaneous deletion and S4 has a constructed deletion in the 0.0 to 4.0 map unit region. Constructed strains which had these deleted sequences restored did immortalize common marmoset peripheral blood lymphocytes. Thus, the nononcogenic deletion mutants are defective for immortalization. This system should facilitate attempts to define the sequences responsible for immortalization and to determine their function.

Animals↗
PubMed1986

In vivo administration of lymphocyte-specific monoclonal antibodies in nonhuman primates. In vivo stability of disulfide-linked immunotoxin conjugates.

The stability in vivo and circulatory clearance of immunotoxins were assessed in rhesus monkeys. The immunotoxins studied were T cell-specific monoclonal anti-T11 antibodies conjugated by disulfide linkage to ribosome-inactivating toxins. Intact immunotoxin was detectable in the circulation of the monkeys following a single intravenous infusion. This was demonstrated by quantitative flow-cytometric analysis, gel-filtration, and sodium dodecyl sulfate-gel electrophoresis. This intact conjugate was shown to be functional in the plasma of the infused animals in an in vitro cytotoxicity assay. However, a number of factors contributed to bring the level of circulating immunotoxin to a less than optimal level. When conjugated to a ribosome-inactivating toxin, the antibody was cleared more rapidly than was the native antibody. Furthermore, following infusion, some breakdown of the conjugate occurred, resulting in the generation of detectable levels of circulating free antibody. The present data indicate the feasibility of using immunotoxins as therapeutic tools in man.

Animals↗
PubMed1986

In vivo administration of lymphocyte-specific monoclonal antibodies in nonhuman primates. Delivery of ribosome-inactivating proteins to spleen and lymph node T cells.

The selective delivery in vivo of a T lymphocyte-specific monoclonal antibody and immunotoxin conjugates to T cells in lymph node and spleen was assessed in rhesus monkeys. A transient coating of all T lymphocytes in the lymph nodes and spleens of healthy rhesus monkeys could be achieved after infusion of unconjugated anti-T11. Because derivatized antibody is cleared more rapidly than unconjugated antibody, it was necessary to infuse a higher dose of immunotoxin than antibody alone to achieve saturation of the lymphocyte binding sites with anti-T11. When sufficient antibody-toxin conjugate was infused, toxin was readily demonstrable on lymph node and spleen T cells by 16 h after infusion. This demonstration that toxins can be successfully delivered with specificity to target T cell populations in the monkey suggests that killing of restricted cell populations in vivo should be feasible.

Animals↗
PubMed1986

Humoral immune responses to T cell tropic retrovirus simian T lymphotropic virus type III in monkeys with experimentally induced acquired immune deficiency-like syndrome.

The T cell tropic retrovirus of macaque monkeys simian T lymphotropic virus type III (STLV-III) has morphologic, growth, and antigenic properties indicating that it is related to human T cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), the etiologic agent of the acquired immune deficiency syndrome (AIDS) of humans. STLV-III has recently been shown to induce an AIDS-like disease in macaque monkeys. In this study the humoral immune responses of six experimentally infected monkeys have been characterized to determine whether certain parameters of the antibody response to the virus might be predictive of the clinical outcome of this infection. Two distinct patterns of antibody responses were found. Four animals that died within 160 d of inoculation developed low titer anti-STLV-III antibody responses that recognized only the viral envelope protein, and progressive declines in total plasma IgG levels and absolute peripheral blood T4 lymphocyte numbers. The two animals that lived longer (one died at 352 d, the other remains alive at 430 d) developed high titer anti-STLV-III antibody responses that recognized both viral envelope and core proteins, increases in total plasma IgG, and a later decrease in number of peripheral blood T4 lymphocytes. Interestingly, the single animal that has remained clinically healthy after infection was the only one to develop detectable STLV-III neutralizing antibodies.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Lymphoproliferative syndrome in an immunodeficient rhesus monkey naturally infected with an HTLV-III-like virus (STLV-III).

A rhesus monkey with a naturally acquired STLV-III infection developed immunosuppression and a lymphoproliferative syndrome characterized by progressive lymphadenopathy and widespread visceral mononuclear cell infiltration. On microscopic examination, diffuse sheets of plasmacytoid lymphoblasts obliterated the sinuses and follicles of the nodes, replaced normal cellular elements of the spleen, bone marrow, and thymus, and infiltrated the lung, liver, kidney, salivary gland, pancreas, thyroid, stomach, and tongue. Immunohistologic studies indicated that the predominant cell in these infiltrates was a B lymphocyte, of oligo- or polyclonal origin. Similar but less extreme lymphoproliferative abnormalities were seen at necropsy in a substantial number of other animals with naturally occurring macaque immunodeficiency syndrome. The present case represents the first prospectively studied monkey with a naturally acquired simian T lymphotropic virus type III infection and illustrates an important manifestation of disease associated with such an infection.

Acquired Immunodeficiency Syndrome↗
PubMed1985

A naturally occurring bone marrow-chimeric primate. II. Environment dictates restriction on cytolytic T lymphocyte-target cell interactions.

Restriction on cytolytic T lymphocyte (CTL)-target cell-interactions are studied in the primate S. oedipus, a naturally occurring A + B----A bone marrow-chimeric species. We show that the T cell, B cell, and myelomonocytic progenitor cell populations are chimeric in this species. We selected animals for study that are populated by fully major histocompatibility complex (MHC)-disparate hematopoietic cell populations, using a functional assay system. We then developed an in vitro system for analyzing at the clonal level the genetic restrictions on the trinitrophenyl-specific CTL-target cell interactions of this species. In this system, we have shown that tolerance to foreign MHC determinants was not, of itself, sufficient to facilitate the generation of CTL specific for target cells expressing those foreign MHC determinants. Rather, a marked preference for the expansion of CTL clones with a restriction for target cells bearing the host animals' MHC determinants was seen. Hematopoietically derived cells did not affect the repertoire of these T lymphocytes. These studies represent the first demonstration of the phenomenon of an environment dictating interactional restrictions on CTL in a naturally occurring bone marrow-chimeric animal. This is also the first demonstration of the profound influence of the environment on the repertoire of the T lymphocyte in a primate species.

Animals↗
PubMed1985

Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III.

The T-cell tropic retrovirus of macaque monkeys STLV-III has morphologic, growth, and antigenic properties indicating that it is related to HTLV-III/LAV, the etiologic agent of the acquired immune deficiency syndrome (AIDS) in humans. Four of six rhesus monkeys died within 160 days of STLV-III inoculation with a wasting syndrome, opportunistic infections, a primary retroviral encephalitis, and immunologic abnormalities including a decrease in T4+ peripheral blood lymphocytes. These data show that an immunodeficiency syndrome can be produced experimentally in a nonhuman primate by an agent from the HTLV-III/LAV group of retroviruses. The STLV-III-macaque system will thus provide a useful model for the study of antiviral agents and vaccine development for human AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Isolation of T-cell tropic HTLV-III-like retrovirus from macaques.

The isolation of a T-cell tropic retrovirus from three immunodeficient macaques and one macaque with lymphoma is described. The morphology, growth characteristics, and antigenic properties of this virus indicate that it is related to the causative agent of acquired immune deficiency syndrome in humans (HTLV-III or LAV). This virus is referred to as simian T-lymphotropic virus type III (STLV-III) of macaques. The existence of a cytopathic, T-cell tropic virus resembling HTLV-III in monkeys may facilitate study of disease induction and vaccine development in an animal model.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III.

Human T-lymphotropic virus type III (HTLV-III) is thought to play an etiologic role in the development of the acquired immune deficiency syndrome (AIDS). In this study the serologic characterization of a new simian retrovirus that is related to HTLV-III is described. This new virus, here referred to as STLV-III, was isolated from sick macaques at the New England Regional Primate Research Center. Radioimmunoprecipitation analysis revealed STLV-III-specific proteins of 160, 120, 55, and 24 kilodaltons, all similar in size to the major gag and env proteins of HTLV-III. These antigens were recognized by representative macaque serum samples and human reference serum samples positive for HTLV-III antibodies. Monoclonal antibodies directed to p24, the major core protein of HTLV-III, also immunoprecipitated a 24-kilodalton species in lysates of cells infected with the macaque virus. This HTLV-III-related virus, which naturally infects a nonhuman primate species, may provide a useful model for the study of HTLV-III and the pathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Definition of the T-lymphocyte inducer of suppression in primates using a monoclonal antibody.

Since some of the conserved antigens between man and phylogenetically lower primate species may be more immunodominant on lymphocytes of the lower primate species, we reasoned that immunization of mice with lymphocytes from lower primates might prove a useful strategy for developing monoclonal antibodies which recognize functionally important structures on both human and nonhuman primate lymphocytes. In employing this approach for the development of monoclonal antibodies, we have developed the antibody anti-2H4 which recognizes a structure on both T on non-T mononuclear cells of a wide array of primate species. 2H4+ rhesus monkey T lymphocytes exhibited a greater proliferative response to lectin and alloantigenic stimulation than 2H4- cells, suggesting that anti-2H4 might separate primate T lymphocytes into functionally distinct cell populations. In fact, helper activity for antibody production by rhesus monkey B lymphocytes in response to pokeweed mitogen (PWM) resided in the 2H4- T-cell population. Furthermore, the 2H4+ T-lymphocyte population activated the suppressor function of T8+ rhesus monkey cells. The fact that the surface antigen which defines this T-cell subset is widely conserved in nonhuman primates suggests that anti-2H4 recognizes a functionally important structure.

Animals↗
PubMed1985

In vitro growth characteristics of simian T-lymphotropic virus type III.

The type C retrovirus simian T-lymphotropic virus type III (STLV-III) has been isolated recently from immunodeficient macaque monkeys at the New England Regional Primate Research Center. The present studies were done to define the in vitro growth characteristics of this agent. STLV-III replicates efficiently in interleukin 2-dependent T-cell cultures of macaque peripheral blood lymphocytes (PBL), less efficiently in such cultures of human and gibbon PBL, and inefficiently in baboon PBL. No replication, as assessed by measuring reverse transcriptase activity in these culture supernatants, could be detected in similarly maintained cultures of chimpanzee, squirrel monkey, and cotton-top tamarin PBL. Like the human acquired immunodeficiency syndrome (AIDS) virus, human T-cell lymphotropic virus III/lymphadenopathy-associated virus (HTLV-III/LAV), STLV-III replicates in T4+ but not T8+ lymphocytes and its infection of macaque and human lymphocytes can be blocked with monoclonal anti-T4 antibodies. STLV-III differs from the human AIDS virus, however, in its apparent inability to grow in the Epstein-Barr virus-transformed B lymphocytes tested, the differing range of nonhuman primate T-cell populations that support its growth, and its less striking toxicity for T lymphocytes. These studies provide further characterization of an agent that will be extremely important in facilitating the development of vaccines and antiviral therapy for AIDS.

Adult↗