Development of large granular lymphocytes in owl monkeys following EBV inoculation.
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Animals↗
Biomedical subjects
N L Letvin
Publications and source records attributed to N L Letvin.
A naturally occurring bone-marrow-chimeric primate. I. Integrity of its immune system.
The New World primate species Saguinus oedipus, the cotton-top tamarin, has a high incidence of spontaneously occurring adenocarcinoma of the colon and develops a fatal lymphoproliferative syndrome following infection with various herpes viruses. Some investigators have linked such disease susceptibilities to abnormalities in the immune function of the cotton-top tamarin that may result from the natural bone marrow chimerism that occurs in this species. The present studies were initiated to establish conditions for studying the immune system of these primates and to assess the integrity of this system. First, we document the state of bone marrow chimerism of S oedipus. We then show that standard in vitro assays of lymphocyte function can be done with cells from this animal. Proliferative T cell assays, cytotoxic T lymphocyte (CTL) assays, and measurements of CTL precursor frequency all indicate that the immune system of this animal functions normally. Finally, we demonstrate in vitro the tolerance of lymphocytes from one S oedipus for the cells of its twin. The ability to manipulate tamarin blood cells in vitro will allow future investigation into mechanisms of immune tolerance and major histocompatibility complex restrictions on cell cooperation in this species.
Animals↗
Retrovirus D/New England and its relation to Mason-Pfizer monkey virus.
Seventeen isolates of retrovirus D/New England have been obtained from three species of macaques at the New England Regional Primate Research Center. Seven of the isolates were obtained from macaques who subsequently died with the macaque immunodeficiency syndrome; other isolates were obtained from macaques with less severe or other forms of illness. Attempts to isolate type D retrovirus from peripheral lymphocytes of 97 apparently healthy macaques have not been successful. Cloned DNA was prepared from Hirt supernatants of cells infected with one of these isolates (D/New England 398). By restriction endonuclease analysis, cloned pD398 DNA represented full-length viral DNA with one long terminal repeat. A detailed restriction endonuclease map of pD398 was derived and compared with a map of the cloned Mason-Pfizer monkey virus genome. Forty-six percent (13 of 28) of restriction endonuclease sites were found to be conserved when these related viruses were compared. Five of the D/New England isolates, including those from three different macaque species, were examined for strain variability by restriction endonuclease typing. Comparison of over 30 restriction endonuclease sites has not distinguished any of these D/New England isolates. It thus appears that a single strain of type D retrovirus is infecting three different species of macaques in the New England colony. Markedly reduced cross-hybridization was observed between cloned pD398 and Mason-Pfizer monkey virus DNAs at high stringency; this reduced cross-hybridization was localized to the pol-env regions of the genome. Only very weak hybridization of D/New England DNA to cloned squirrel monkey type D retrovirus DNA could be detected even at low-stringency conditions. What role type D retrovirus plays in the immunodeficiency syndrome of macaques remains to be determined.
Animals↗
Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.
To determine the influence of cell cycle-specific agents on primate hematopoiesis and fetal hemoglobin production, two juvenile cynomolgus monkeys (Macaca fascicularis) were repeatedly bled to maintain their hemoglobins at approximately 6.5 g/dl and fetal hemoglobin levels at 3-5%. Six separate 5-d courses of hydroxyurea at 100 mg/kg per d were then administered over the next 200 d while phlebotomy was continued. These courses of hydroxyurea progressively raised the fetal hemoglobin levels to 17 and 18%, respectively. The drug had very little effect on the frequency of immature erythroid progenitors (BFU-E) in the bone marrow, but caused a marked reduction in the frequency of later progenitors (CFU-E) and a transient fall in the reticulocyte count. Following the courses of hydroxyurea, the number of F cells and the fetal hemoglobin level fell to base line over a period of 4 wk. Two control animals which were not phlebotomized showed no detectable increase in F cells or fetal hemoglobin when treated with the same regimen of hydroxyurea. A 5-d course of 5-azacytidine at 8 mg/kg per d was then given to each of the phlebotomized animals. This produced a more profound, albeit transient, reticulocytopenia, a fall in the CFU-E/BFU-E ratio, and a prompt increase in the fetal hemoglobin to levels even higher than were seen following a single 5-d course of hydroxyurea at 100 mg/kg/d. Subsequently, the animals were given a single dose of vinblastine at 0.4 mg/kg which reduced reticulocytes and CFU-E to the same extent as hydroxyurea; however, vinblastine at this dose had no effect on hemoglobin F (HbF) production. In contrast, when vinblastine was administered to the phlebotomized monkeys as a 5-d course at 0.2 mg/kg/d, prolonged reticulocytopenia followed by dramatic F cell and HbF responses were seen. Combinations of single dose vinblastine and a 5-d course of hydroxyurea were subsequently administered using two different schedules. When the animals received vinblastine on the first day of a 5-d course of hydroxyurea, the F cell response was double that seen following hydroxyurea treatment alone. In contrast, when vinblastine was administered on the final day of hydroxyurea treatment, the magnitude of the F cell response was the same as that which occurred following hydroxyurea treatment alone, but the onset of the rise was delayed for 4 d and HbF/F cell response was much higher. These results establish several important features of the fetal hemoglobin response to cytotoxic agents in the primate model. The response requires accelerated erythropoiesis and is preceded by transient reticulocytopenia. The response is produced by S phase- and M phase-specific agents when given in sufficient doses and at appropriate schedules. Passage of erythrocyte progenitors through M phase appears to be necessary for expression of the effect produced by S phase agents. The fetal hemoglobin response induced by cytotoxic drug administration occurs during the recovery of erythropoiesis following marrow suppression.
Animals↗
The isolation and characterization of the human suppressor inducer T cell subset.
Immunization of mice with lower primate lymphoid cells has provided a useful strategy for raising monoclonal antibodies against functionally important surface determinants on human T lymphocytes. We have developed a monoclonal antibody, anti-2H4, which defines functionally unique human T cell subsets. This anti-2H4 antibody was reactive with approximately 42% of unfractionated T cells, 41% of T4+ inducer cells, and was reactive with approximately 54% of T8+ cytotoxic/suppressor population. Anti-2H4 was not reactive with human thymocytes, but reacted with subsets of peripheral blood B cells and null cells. This antibody subdivided peripheral blood T4+ cells into two functionally distinct populations. The T4+2H4+ subset proliferate well to concanavalin A (Con A) stimulation, but poorly to soluble antigen stimulation, and provides poor help to B cells for PWM-induced Ig synthesis. The T4+2H4- subset, in contrast, proliferates poorly upon stimulation with Con A, but well on exposure to soluble antigen, and provides a good helper signal for PWM-induced Ig synthesis. What is, perhaps, most important, the T4+2H4+ subset functions as the inducer of the T8+ suppressor cells. Previous attempts to define the latter subset of cells has relied heavily on the use of specific autoantibodies present in the sera of patients with juvenile rheumatoid arthritis (JRA) and systemic lupus erythematosus (SLE). The present results suggest that anti-2H4 antibody defines the human suppressor induced subset of lymphocyte previously described as T4+JRA+. Last, the results reemphasize the previously documented remarkable structural conservation of certain T cell-specific determinants on lymphocytes of phylogenetically distant primates.
Animals↗
The isolation and characterization of the human helper inducer T cell subset.
Monoclonal antibody anti-4B4 was produced by fusing NS1 myeloma with spleen cells of a mouse immunized with Saguinus oedipus lymphocyte. This anti-4B4 antibody defines a 135-KD cell surface protein that is widely distributed throughout the hematopoietic system. More importantly, anti-4B4 is reactive with functionally unique human T cell subsets. Anti-4B4 antibody was reactive with approximately 41% of unfractionated T cells, 41% of T4+ inducer cells, and approximately 43% of T8+ cytotoxic/suppressor population. This antibody subdivided peripheral blood T4+ cells into two functionally distinct populations. The T4+4B4+ subset proliferates relatively poorly upon stimulation with Con A and autologous cell antigens (AMLR) but well on exposure to soluble antigens, and it provides a good helper signal for PWM-induced Ig synthesis. The T4+4B4- subset, in contrast, proliferates well to Con A stimulation and autologous cell antigen (AMLR) but relatively poorly to soluble antigen stimulation, and provides little help to B cells for PWM-induced Ig synthesis. The T4+4B4- subset is largely 2H4+ and functions as the inducer of the T8+ suppressor cells. Thus, the present results suggest that one can divide the human T4 population into two major subsets that are phenotypically and functionally distinct, the human helper inducer subset (T4+4B4+/H.I.) and its reciprocal population defined by anti-2H4, the suppressor inducer subset (T4+2H4+/S.I.).
Animals↗
In vivo administration of lymphocyte-specific monoclonal antibodies in nonhuman primates: I. Effects of anti-T11 antibodies on the circulating T cell pool.
The effects of in vivo administration of three monoclonal antibodies specific for T11, the E rosette receptor on T lymphocytes, were examined in the rhesus monkey (Macaca mulatta). These three monoclonal antibodies were of different isotypes and were shown in in vitro studies to have differing affinities for the monkey T11 structure. Furthermore, each antibody induced antigenic modulation of T11 from the cell membrane of the lymphocytes to varying degrees in vitro. In vivo infusion of each of these antibodies into normal rhesus monkeys caused remarkably different effects on the circulating T lymphocyte pool. Infusion of these antibodies at doses of 2 mg/kg caused the coating of circulating T lymphocytes with antibody, the modulation of T11 off the T cell surface and the transient clearance of T cells from the circulation. Yet, the variation in the extent to which these effects were seen with these different antibodies indicates that extrapolating from studies of the in vivo use of one antibody to the use of another may be quite difficult. These studies clearly indicate the strengths of this nonhuman primate system for exploring the uses of monoclonal antilymphocyte antibodies as therapeutic agents. They, however, also demonstrate that differences may exist in the affinity of a particular antibody for homologous lymphocyte surface structures in humans and in a nonhuman primate species. These differences may make it difficult to predict the precise effects that the infusion of an antibody will cause in humans on the basis of alterations it induces in nonhuman primates.
Animals↗
Lymphoma in macaques: association with virus of human T lymphotrophic family.
Human T-cell leukemia virus has been linked with adult T-cell leukemia-lymphoma (ATLL), a tumor of mature T cells that occurs at elevated rates in southwestern Japan and in the Caribbean Basin. Human T-cell leukemia virus (HTLV) or a closely related virus, has also been found in varying proportions of healthy individuals of several species of Old World monkeys. In the present study, conducted with macaques from Taiwan and the New England Regional Primate Research Center, antibodies to membrane antigens of HTLV-infected cells (HTLV-MA) were found in 11 of 13 macaques with malignant lymphoma or lymphoproliferative disease but in only 7 of 95 of healthy macaques. This indicates that antibodies to HTLV are significantly associated with the development of naturally occurring lymphoid neoplasms in at least some species of nonhuman primates.
Animals↗
Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea.
The increase in fetal-hemoglobin synthesis in patients with beta-thalassemia or sickle-cell anemia induced by 5-azacytidine has been attributed to hypomethylation of DNA in the region of the gamma-globin genes. To determine whether hydroxyurea, a cytotoxic/cytostatic drug that does not influence DNA methylation, might stimulate fetal-hemoglobin synthesis, we phlebotomized two juvenile cynomolgus monkeys to induce anemia and reticulocytosis and then treated them with hydroxyurea. Immediately after phlebotomy was initiated, there was a rise in the level of F cells, which stabilized at an average value of 13 per cent in one animal and 20 per cent in the other during a two-month control period. Fetal hemoglobin gradually rose from undetectable values before bleeding to 3 per cent in one animal and 5 per cent in the other. Sixty-two days after initiation of phlebotomy, hydroxyurea (50 mg per kilogram of body weight per day for five days) induced only a small and transient increase in F cells and fetal hemoglobin. Two weeks later, however, a similar course (100 mg per kilogram per day) resulted in a prompt and dramatic increase in both indexes. These results strongly suggest that S-phase-specific cytotoxic/cytostatic drugs increase fetal hemoglobin by a mechanism that does not involve inhibition of DNA methylation.
Anemia↗
A new type D retrovirus isolated from macaques with an immunodeficiency syndrome.
Macaque monkeys with the recently described acquired immunodeficiency syndrome show a marked defect in T-lymphocyte function and die with opportunistic infections and lymphoproliferative abnormalities. In the study described here a new type D retrovirus was isolated from two Macaca cyclopis with this syndrome. This virus is related to, but distinct from, Mason-Pfizer monkey virus, a type D retrovirus previously isolated from a mammary tumor of a rhesus monkey (Macaca mulatta).
Animals↗
Surface antigen changes during B-lymphocyte activation in primates.
It is shown that B-cell-specific surface antigens are conserved on lymphocytes from phylogenetically distant primate species. Characterization of the expression of those antigens on the surface of simian B lymphocytes has led to two observations with important implications for human B-cell physiology. First, lectin stimulation in vitro or antigen stimulation in situ in lymph nodes drives a population of human B lymphocytes to express the B2 but not the B1 antigen on its surface. Second, under pathologic circumstances, this activated B cell can be found in the peripheral blood of monkeys. Thus, the "B2 only" cell defines an activated B lymphocyte whose presence may provide useful diagnostic information concerning pathologic processes.
Animals↗
Delineation of lymphocyte subsets in lymph nodes of nonhuman primates.
Monoclonal antibodies which recognize specific surface antigens on human lymphocytes were used with an avidin-biotin immunoperoxidase technique to stain lymph nodes from nonhuman primates. Cells in lymph nodes from three macaque species and two new-world primate species could be stained to define T11, T4, T8, and B1 lymphocyte subsets. This approach will facilitate the study of many important spontaneous and experimentally induced diseases of nonhuman primates.
Animals↗
Clinical and pathologic features of an acquired immune deficiency syndrome (AIDS) in macaque monkeys.
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Acquired Immunodeficiency Syndrome↗
Hematogenous hexamitiasis in a macaque monkey with an immunodeficiency syndrome.
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Acquired Immunodeficiency Syndrome↗
An acquired immune deficiency syndrome of macaque monkeys.
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Acquired Immunodeficiency Syndrome↗
Experimental infection of rhesus monkeys with type D retrovirus.
The naturally occurring immunodeficiency syndrome of macaque monkeys is an important animal model for the acquired immunodeficiency syndrome in humans. A new type D retrovirus, distinct from Mason-Pfizer monkey virus, has been isolated from affected animals at the New England Regional Primate Research Center. We now report the results of experimental infection of macaques with retrovirus D/New England after 13 months of study. Inoculated macaques developed lymphadenopathy without follicular hyperplasia, profound neutropenia, and a transient decrease in peripheral blood lymphocyte blastogenic responsiveness. Despite our varying the strain of virus, the manner in which the virus was grown, the size of the inoculum, and the age of the inoculated animals, infected macaques have not developed opportunistic infections or profound, prolonged loss of T cell function, key features of the macaque immunodeficiency syndrome. Therefore, experimental infection of naive macaques with D/New England has not reproduced the naturally occurring macaque immunodeficiency syndrome.
Acquired Immunodeficiency Syndrome↗
Animal models of AIDS.
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Acquired Immunodeficiency Syndrome↗
Lyt-1 cells mediate acute murine experimental allergic encephalomyelitis.
Adult SJL/J mice were depleted of T lymphocytes and were reconstituted with Lyt-1, Lyt-2, or Lyt-1 + Lyt-2 cells. After immunization with MSCH, severe acute EAE developed in the Lyt-1- and the Lyt-1 + Lyt-2-reconstituted mice. Only 25% of the Lyt-2-reconstituted mice developed signs of EAE, and in those EAE onset was delayed. Thus, Lyt-1 cells mediate EAE in the mouse.
Acute Disease↗