Functional and Morphological Development of Lymphoid Tissues and Immune Regulatory and Effector Function in Rhesus Monkeys: Cytokine-Secreting Cells, Immunoglobulin-Secreting Cells, and CD5⁺B-1 Cells Appear Early in Fetal Development

Abstract

Little is known regarding the timing of immune ontogeny and effector function in fetal humans and nonhuman primates. We studied the organization of lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus monkey fetuses during the second and third trimesters (65 to 145 days of gestation; term = 165 days). Immunoglobulin-secreting and cytokine-secreting cells were detected at day 80. The thymus, spleen, lymph nodes, and intestinal mucosa were examined for cells expressing CD3, CD5, CD20, CD68, p55, and HLA-DR. In the spleens of 65-day-old fetuses (early second trimester), the overwhelming majority of total lymphocytes were CD5(+) CD20(+) B-1 cells. The remaining lymphocytes were CD3(+) T cells. By day 80, splenic B and T cells were equal in number. Intraepithelial CD3(+) CD5(-) T cells and lamina propria CD20(+) CD5(+) B cells were present in the intestines of 65-day-old fetuses. By day 80, numerous CD20(+) CD5(+) B cells were present in the jejunums and colons and early lymphocyte aggregate formation was evident. The spleens of 80- to 145-day-old fetuses contained immunoglobulin M (IgM)-secreting cells, while IgA-, IgG-, interleukin-6-, and gamma interferon-secreting cells were numerous in the spleens and colons. Thus, by the second trimester, the lymphoid tissues of the rhesus monkey fetus have a complete repertoire of properly organized antigen-presenting cells, T cells, and B cells.

Simian Immunodeficiency Virus Infection in Neonatal Macaques

“…recently reported large numbers of functional (cytokine-and/or immunoglobulin-secreting) T cells, B cells, and antigen-presenting cells in the intestine and spleens of second-trimester macaque fetuses (17). The findings reported here demonstrating an abundance of CD4 ϩ T-helper cells in various lymphoid tissues of newborn macaques, many of which express HLA-DR, also support that the newborn immune system is adequately primed to mount an immune response.…”

“…However, levels of CD28 and CD38 were similar to levels observed on lymphocyte subsets from adult macaques (unpublished observations). Combined, these data and other recent data (17) suggest that neonatal lymphocytes express normal levels of costimulatory and activation molecules and are capable of mounting immune responses at birth.…”

“…Furthermore, levels of soluble L-selectin were shown to be higher in HIV-infected neonates than in uninfected children (11). More recent studies have demonstrated that functional, cytokine-and/or immunoglobulin-secreting cells develop very early in utero in nonhuman primates and that these cells may be functional at birth (17). Since HIV and simian immunodeficiency virus (SIV) replicate most efficiently in activated CD4 ϩ T cells of adults (32,33,46) and children (29), increased levels of CD4 ϩ T-cell activation could, at least partially, explain the higher viral loads in infected neonates.…”

Developmental and reproductive toxicology studies in nonhuman primates

“…Rhesus macaques (Macaca mulatta) or marmosets (Callithrix jacchus) can also be used although there are certain limitations of using these species, such as seasonal breeding in rhesus macaques (Henck et al, 1996;Wickings and Nieschlag, 1980) and small size and blood volume in marmosets (Fuchs and Weinbauer, 2006;Zuhlke and Weinbauer, 2003). The embryology and fetal development between cynomolgus and rhesus monkeys is very similar Geijsberts, 1981, 1985;Makori et al, 1996Makori et al, , 2003Tarantal and Hendrickx, 1988a,b), and thus the basic research findings in one can be applied to the other in the context of the current report. Baboons and chimpanzees are not acceptable species for DART testing because of their lack of availability, lack of historical control data, and because of the ethical considerations associated with the use of these species.…”

Poor Immune Responses of Newborn Rhesus Macaques to Measles Virus DNA Vaccines Expressing the Hemagglutinin and Fusion Glycoproteins

“…The gestation period in rhesus monkeys is 5 months, with hallmarks of fetal development that are similar to those of humans (41). The nature of the vaccine is important, as several vaccines are successfully delivered at birth (7).…”