Immunological Responses to Injury and Grafting in the Central Nervous System of Nonhuman Primates

Abstract

Allogeneic transplantation for the therapy of human Parkinson's disease is being considered as a viable approach at several clinical centers worldwide. As an attempt to understand the basic biology of central nervous system (CNS) transplantation, our laboratory has developed an experimental nonhuman primate model for human Parkinson's disease and carried out preliminary studies directed at evaluating the potential pathology at the graft site. In addition, studies have been conducted to examine whether such transplantation procedures lead to specific and/or nonspecific immunologic sensitization of the host or results in generalized immunosuppression. Groups of rhesus macaques (Macaca mulatta) were either controls operated (n = 6), autografted with adrenal medullary and peripheral nerve tissue (n = 3), or allografted with fetal mesencephalic tissue (n = 6). Immunohistological studies demonstrated the presence of mononuclear cell infiltrates as early as 1 wk and up to 1 yr postoperatively, although the frequency of the infiltrating cells declined with time. The infiltrates consisted of variable numbers of cells which express CD2+, CD3+, CD4+, CD8+, CD19+, CD22+, CD25+, and CD68+. There appeared to be no difference in the frequency, kinetics, or phenotype of the infiltrating cells in operative controls compared with recipients of auto- or allografts. Tissue sections obtained postoperatively showed low levels of major histocompatibility complex (MHC) Class I antigens and no detectable level of MHC-Class II antigens in neural tissue. A small aliquot of tissue from the operative site was placed in vitro with media containing interleukin-2 (IL-2), which led to the exudation and growth of mononuclear cells that were predominantly CD4+ cells. Phenotypic studies of peripheral blood mononuclear cells (PBMC) from operative controls, auto- and allograft recipient monkeys performed at varying time periods postoperatively failed to show differences in the frequencies of subsets of T-cells, B-cells, NK-cells, or monocytes. Studies on aliquots of the same PBMC failed to show major functional differences in NK-cells, LAK cells, or response to polyclonal mitogens. Finally, recipients of allogeneic mesencephalic grafts failed to show evidence of donor-specific humoral or cellular sensitization. These data indicate that transplantation of autograft adrenal or allograft fetal mesencephalic tissues in the CNS of nonhuman primate did not induce detectable donor-specific sensitization nor nonspecific immunosuppression.

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Do Not Differentiate Into Neural Cell Types or Integrate Into the Retina After Intravitreal Grafting in Neonatal Rats

“…Moreover, the issue of immune or infl ammatory responses of the host animals to cell or tissue grafts to presumably immuno-privileged sites including the brain and eye remains an important issue that clearly needs further investigation [20][21][22][23].…”

An overview of central nervous system transplantation in human disease

“…Nonetheless, it cannot be assumed that the graft will be accepted. Limited migration of mononuclear cells can be seen at graft sites, [5] although a humoral response has not been identified in humans. [1] Evidence derived from human trials does suggest that immunosuppression is not required, [27] but the issue remains controversial.…”

Neurotransplantation and Protective Therapy for Movement Disorders

“…43 Evidence from primate models suggests that allografts in the brain do not routinely evoke donor-specific lymphocytotoxic sensitization. 44,45 Immunologic response to fetal CNS allografts in primates may be restricted to a local inflammatory reaction. 41,[44][45][46] A study of several human CNS-grafted patients also lacked humoral or cellular systemic sensitization.…”

“…44,45 Immunologic response to fetal CNS allografts in primates may be restricted to a local inflammatory reaction. 41,[44][45][46] A study of several human CNS-grafted patients also lacked humoral or cellular systemic sensitization. 46 Autopsy data also fail to show rejection, 37 but both microglia and peripheral immune cells were observed in the grafts.…”

“…A similar response is observed in both FM-grafted MPTP primates and sham-operated monkeys in response to CNS trauma. 44 The use of multiple fetuses and staggered grafting times may result in higher chance for rejection. The use of immunosuppressive therapy for fetal CNS grafting remains controversial.…”