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.

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.

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.

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.

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.

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.

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.

Experimental transmission of macaque AIDS by means of inoculation of macaque lymphoma tissue.

Acquired immuno-deficiency syndrome (AIDS) of macaques, an animal model for human AIDS, was transmitted to previously healthy macaque monkeys by means of inoculation of either tissue or a cell-free filtrate of a macaque lymphoma. The recipients showed evidence of profound lymphocyte dysfunction or died with infections from such opportunistic agents as Candida albicans, Cryptosporidium, and cytomegalovirus.

Acquired immunodeficiency syndrome in a colony of macaque monkeys.

A naturally occurring immunodeficiency syndrome has been seen in a captive colony of macaque monkeys. This syndrome is seen primarily in the species Macaca cyclopis. Affected animals died with lymphomas (a rare disease in macaques) or such opportunistic infections as Pneumocystis carinii and noma (necrotizing gingivitis). These M. cyclopis exhibited anemia, neutropenia, and a circulating bizarre immature monocyte. In addition, liver function tests suggested hepatitis. Pokeweed mitogen-, concanavalin A-, and xenogeneic cell-stimulated proliferative responses by lymphocytes of animals with the syndrome were dramatically diminished. The T4 (helper, inducer)/T8 (suppressor, cytotoxic) ratio in the peripheral blood mononuclear T-cell populations of M. cyclopis in this colony are decreased when compared with those from either Macaca mulatta in the same colony or normal humans. Epidemiologic evidence implicates a common source agent in this syndrome. The similarity of this syndrome in macaques to human acquired immunodeficiency syndrome suggests that it may provide an important model for studying the human syndrome.