Cytotoxic and immunoregulatory function of intestinal lymphocytes in Chlamydia trachomatis proctitis of nonhuman primates.

To study the role of natural killer cells and immunoregulatory T cells in the pathogenesis of proctitis due to Chlamydia trachomatis (L2 serovar), lymphocytes were obtained from the rectal mucosa and other sites of nonhuman primates and studied by using phenotypic and functional assays. In animals with lymphogranuloma venereum (LGV) proctitis, the percentage of lymphocytes with the natural killer cell phenotype (Leu-11+) was not significantly higher at any site in LGV infection, and natural killer cell function of lymphocytes isolated from the rectum was lower during LGV infection. This was not due to the suppressive effect of factors in serum, rectal lymphocytes, or LGV elementary bodies. In studies of regulatory T cells, the Leu-3+/Leu-2+ ratio was lower in the peripheral blood and the spleen during LGV infection, but the ratio did not decrease in lamina propria T cells. Both peripheral blood and rectal lymphocytes had higher helper T-cell function for polyclonal immunoglobulin G (IgG) synthesis in pokeweed mitogen-stimulated cultures 2 weeks following LGV infection. Increased suppressor T-cell function for pokeweed mitogen-stimulated IgG synthesis was found only in the peripheral blood of animals 2 weeks after infection, but not in isolated rectal lymphocytes. These results indicate that in LGV proctitis natural killer cells are not an important component of the inflammatory infiltrate at the site of infection, and helper T-cell function increases in peripheral blood and rectal lymphocytes.     

Immunoregulatory activity of CpG oligonucleotides in humans and nonhuman primates

Oligodeoxynucleotides (ODN) containing CpG motifs mimic the ability of microbial DNA to activate the innate immune system. The resultant response limits the early spread of infectious organisms while promoting the development of adaptive immunity. CpG ODN show promise as vaccine adjuvants and in the treatment of asthma, allergy, infection, and cancer. Due to evolutionary divergence in CpG recognition between species, CpG ODN that are most active in rodents are poorly immunostimulatory in primates. Thus, evidence that CpG ODN have therapeutic activity in mice must be confirmed in primates. Two distinct types of CpG ODN were identified that stimulate primate PBMC. D-type ODN trigger plasmacytoid DC to secrete IFNalpha, monocytes to mature into functionally active DC, and NK cells to secrete IFNgamma. K-type ODN stimulate B cells and monocytes to proliferate and secrete IgM, IL-10, and/or IL-6. In vivo studies in nonhuman primates indicate that proinflammatory or humoral immune responses can be selectively facilitated by judicious use of these distinct types of ODN.     

Valves in superficial limb veins of humans and nonhuman primates

The venous valves are believed to play an important role in venous function, but their number, position, and spacing in limb veins are reported to be irregular. In this study, the relationship between the number of valves and the length of veins in which they occur was investigated for humans and nonhuman primates. In addition, valve distributions within the superficial veins of the human upper limb were compared with those of the lower limb. Upper and lower limb veins were dissected from adult humans, and forelimb veins were obtained from seven genera of primates. The mean valve index (number of valves per unit length of vein) of the forelimb lateral superficial vein exhibited relatively little variation between humans and primates of a wide range of body sizes and locomotor repertoires. The mean valve index for the lateral superficial vein of the human upper limb is similar to that of the short saphenous vein of the lower limb, and in both veins, the maximum valve index occurs in the most proximal portion of the vein. The relative constancy of the valve index across a range of primate species, and between the upper and lower limbs of humans, may reflect the known constancy of circulatory pressures in mammals. The minimum numbers of valves in superficial veins are only slightly greater than required to limit capillary pressure to below 10 mm Hg, above which pressure the tissue fluid flow would be compromised.     

Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates

Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients.     

Functional morphology of the first cervical vertebra in humans and nonhuman primates

The cervical vertebral column bears or balances the weight of the head supported by the nuchal muscles that partly originate from the cervical vertebrae. The position of the head relative to the vertebral column, and consequently locomotion and posture behavior, could thus be associated with the form of the cervical vertebrae. In spite of this assumption and some empirical indications along these lines, primate vertebral morphologies have been reported to be very similar and not clearly related to locomotion. We therefore study the relationship between the morphology of the first cervical vertebra, the atlas, and the locomotion pattern within primates using a geometric morphometric approach. Our analysis is based on a total of 116 vertebrae of adult Homo sapiens, Gorilla gorilla, Pan troglodytes, Pongo pygmaeus, Hylobates lar, Macaca mulatta, Papio hamadryas, Ateles geoffroyi, and Alouatta palliata. On each atlas, 56 landmarks were digitized and superimposed by Procrustes registration. The resulting shape variables were analyzed by principal component analysis, multivariate regression, and partial least-squares analysis. We found that the nine primate species differ clearly in their atlas morphology and that allometric shape change is distinct between the nonhuman primates and Homo sapiens. We could further identify morphological features that relate to the species' locomotion pattern. Human atlas shape, however, cannot be predicted by an extrapolation of the nonhuman primate model. This implies that either the primate atlas is generalized enough to allow bipedal locomotion or else the human atlas morphology is a unique adaptation different from that in the more orthograde nonhuman primates.     

Comparative genetics of the major histocompatibility complex in humans and nonhuman primates

The major histocompatibility complex (MHC) is one of the most gene‐dense regions of the mammalian genome. Multiple genes within the human MHC (HLA) show extensive polymorphism, and currently, more than 26,000 alleles divided over 39 different genes are known. Nonhuman primate (NHP) species are grouped into great and lesser apes and Old and New World monkeys, and their MHC is studied mostly because of their important role as animal models in preclinical research or in connection with conservation biology purposes. The evolutionary equivalents of many of the HLA genes are present in NHP species, and these genes may also show abundant levels of polymorphism. This review is intended to provide a comprehensive comparison relating to the organization and polymorphism of human and NHP MHC regions.     

Abnormalities of immunoregulatory T cells in disorders of immune function.

We studied a five-year-old girl with several autoimmune disorders and a 16-year-old boy with acquired agammaglobulinemia to determine whether aberrations of immunoregulatory T cells could explain some instances of immunodeficiency or autoimmunity. The normal peripheral blood T-cell population, as defined by specific heteroantiserums, is 20 per cent TH2+ and 80 per cent TH2-. Human suppressor cells are TH2+, whereas helper cells are TH2-. In addition, each subset expresses Ia antigens upon activation. Our patient with autoimmune disease had no demonstrable TH2+ cells, and her lymphocytes could not be induced to suppress. Her circulating T cells were of an activated-helper phenotype, i.e., TH2-,Ia+. In contrast, in the boy with agammaglobulinemia, the T-cell population was predominantly of an activated-suppressor phenotype, i.e., TH2+,Ia+. This patient's T cells abrogated both his own and his histoidentical brother's B-cell secretion of immunoglobulins. We conclude that the characterization of T cells may provide insight into the causes of a number of abnormal immune states in man.     

Parasites and immunoregulatory T cells

Surviving a parasitic infection requires the generation of a controlled immune response. Failure to establish or to maintain homeostatic conditions usually causes disease. Investigation of the immunoregulatory network as the response to the parasitic process or induced by the parasite promises enormous therapeutic benefits for the control of parasitic diseases. Recent findings implicate various populations of regulatory T cells in this homeostatic regulation.     

Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates

Comparative DNA sequence studies between humans and nonhuman primates will be important for understanding the genetic basis of the phenotypic differences between these species. Here we compare approximately 27 Mb of human chromosome 21 with chimpanzee DNA sequences identifying 57 genomic rearrangements (deletions and insertions ranging in size from 0.2 to 8.0 kb) between the two species. These rearrangements are distributed along the entire length of chromosome 21, with approximately 35% found in genomic intervals encoding genes (genic intervals), and have occurred in the genomes of both humans and chimpanzees. Comparison of approximately 9 Mb of human chromosome 21 with orangutan, rhesus macaque, and woolly monkey DNA sequences identified a combined total of 114 genomic rearrangements between humans and nonhuman primates. Analysis of these rearrangements revealed that they are randomly distributed with respect to genic and nongenic intervals and identified one deletion that has likely resulted in the inactivation of a gene (beta1,3-galactosyltransferase) in the woolly monkey. Our data show that genomic rearrangements have occurred frequently during primate genome evolution and significantly contribute to the DNA differences between these species. These DNA rearrangements are commonly found in genic intervals, and thus provide natural starting points for focused investigations of qualitative and quantitative gene expression differences between humans and other primates.     

In utero hematopoietic stem cell transplantation in nonhuman primates: the role of T cells

In utero transplantation of hematopoietic stem cells is a promising treatment for immune and hematologic diseases of fetuses and newborns. Unfortunately, there are limited data from nonhuman primates and humans describing optimal transplantation conditions. The purpose of this investigation was to determine the effect of T-cell number on engraftment and the level of chimerism after in utero transplantation in nonhuman primates. CD34(+) allogeneic adult bone marrow cells, obtained from the sire after G-CSF and stem cell factor administration, were transplanted into female fetal recipients. The average CD34(+) cell dose was 3.0 x 10(9)/kg (range, 9.9 x 10(8) to 4.4 x 10(9)) and the T-cell dose ranged from 2.6 x 10(5) to 1.1 x 10(8)/kg. Chimerism was determined in peripheral blood subsets (CD2, CD13, and CD20) and in progenitor cell populations by using polymerase chain reaction. Chimerism was noted in seven of eight live-born animals. The level of chimerism in the progenitor population was related to the fetal T-cell dose (r = 0.64, p < 0.02). At the lowest T-cell dose (2.6 x 10(5)/kg), no chimerism was detected. As the T-cell dose increased to 10(6-7)/kg, the level of chimerism increased. Adjusting the T-cell dose to 1.1 x 10(8)/kg resulted in fatal graft-versus-host disease (GVHD). The results of this study emphasize the importance of T cells in facilitating donor cell engraftment and in producing GVHD in fetal nonhuman primates. Some animals achieved levels of chimerism in the marrow hematopoietic progenitor cell population that would likely have clinical relevance. However, the levels of chimerism in peripheral blood were too low for therapeutic benefit. Further studies are needed to test methods that are likely to enhance donor cell engraftment and peripheral blood levels of donor cells.     

Effects of ovarian hormones on cognitive function in nonhuman primates

Several studies have suggested that estrogen benefits verbal memory and lowers the risk of Alzheimer's disease in women, and improves cognitive function in animal models. However, the negative outcome of the Women's Health Initiative Memory Study has challenged the rationale for using estrogen as a protective agent against age-related cognitive decline. In view of the limitations of the Women's Health Initiative Memory Study, it is clear that our understanding of estrogen effects would greatly benefit from further interactions between clinical and basic science. Animal models of menopause can provide crucial information regarding the consequences of estrogen loss and replacement on several systems, including cognition. In this paper, I review the evidence that nonhuman primates, who share numerous cognitive and physiological characteristics with humans, can substantially contribute to our understanding of estrogen influences on the brain and cognition. Studies in young adult females suggest that some aspects of cognition fluctuate with the menstrual cycle, but that ovariectomy and estrogen replacement have only modest effects on cognitive function. In contrast, data in aged, naturally or surgically menopausal monkeys indicate that estrogen modulates a broad range of cognitive domains. Neurobiological data are consistent with the cognitive findings and demonstrate an array of morphological and physiological changes in brain areas important for cognition following ovariectomy and/or estrogen replacement. It is concluded that nonhuman primates, by providing a bridge between rodent and human data, constitute invaluable models to further our understanding of hormonal actions on the brain and cognition and to develop effective hormonal interventions against brain and cognitive aging.     

Gonadal hormones influence the emergence of cortical function in nonhuman primates

The role of gonadal hormones in the maturation of the orbital prefrontal cortex (ORB) was studied in normal male and female rhesus monkeys, monkeys given ORB lesions at 50 days of age, and female monkeys given androgen at different ages. Monkeys were tested on an object discrimination reversal task at 75 days of age. Gender influenced the performance of monkeys on the task during normal development and after ORB lesions. Normal males made fewer errors than did normal females. Females treated with androgen performed similarly to normal male monkeys. ORB lesions produced deficits in male monkeys and in females given androgen during late prenatal or early postnatal life, but not in normal females. These findings suggest that gonadal hormones may play an inductive role in the differentiation of higher cortical function in nonhuman primates.     

Effects of Mpl ligands on platelet production and function in nonhuman primates

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates dose-dependentbyinducing megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human TPO, nonpegylated or pegylated recombinant human megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover), platelet TPO receptor density, and marrow megakaryocyte volume, ploidy, number and mass. Mpl ligand therapy sustains normal peripheral platelet concentrations following myelosuppressive chemotherapy in baboons and corrects peripheral platelet counts in HIV-infected chimpanzees with severe thrombocytopenia. Whereas Mpl ligands do not directly induce platelet aggregation in vitro, they enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo following treatment with Mpl ligands. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the direct effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.     

The genetics of immunoregulatory T cells

The immune repertoire of normal, healthy individuals contains autoreactive T cells and natural antibodies that, under normal conditions, are controlled, either through central tolerance or by the activity of immunoregulatory T cells to prevent the onset of autoimmune diseases. Over the years, several types of immunoregulatory T cells have been identified. These include natural CD4+CD25+Foxp3+T (Treg) cells and type 1 NKT cells, which develop in the thymus, as well as acquired immunoregulatory T cells, such as type 1 cells (Tr1), Th3 cells, Ts cells and anergic CD4 T cells, which all appear to be products of peripheral immune activation. While little is understood about the genetics of most types of immunoregulatory T cell, detailed information on the genetic control of NKT and Treg cells is now available and may contribute significantly to our understanding of the aetiology of autoimmune disease.     

Potential effector and immunoregulatory functions of mast cells in mucosal immunity

Mast cells (MCs) are cells of hematopoietic origin that normally reside in mucosal tissues, often near epithelial cells, glands, smooth muscle cells, and nerves. Best known for their contributions to pathology during IgE-associated disorders such as food allergy, asthma, and anaphylaxis, MCs are also thought to mediate IgE-associated effector functions during certain parasite infections. However, various MC populations also can be activated to express functional programs—such as secreting preformed and/or newly synthesized biologically active products—in response to encounters with products derived from diverse pathogens, other host cells (including leukocytes and structural cells), damaged tissue, or the activation of the complement or coagulation systems, as well as by signals derived from the external environment (including animal toxins, plant products, and physical agents). In this review, we will discuss evidence suggesting that MCs can perform diverse effector and immunoregulatory roles that contribute to homeostasis or pathology in mucosal tissues.     

Kinship and behavior in nonhuman primates

Nonhuman primates show significantly more social interaction with matrilineal kin than nonkin. There is little evidence for kin recognition per se, and long-term association, fostered by long periods of biological dependency, strong sociality, and impressive cognitive capacities, is sufficient to account for the correlation between kinship and sociality. Association, as a proximal mechanism, in no way detracts from the adaptive significance of sociality strongly biased toward kin.This work was supported by National Science Foundation Grant BNS 86 16691 and, in part, by NIH grant RR 00165 to the Yerkes Regional Primate Research Center. The Yerkes Primate Center is fully accredited by the AALAC.