Oral administration of alloantigen prolongs kidney allograft survival by generating intragraft regulatory cells.
Date
2001
Authors
Zhou, Juan.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
A major goal of transplantation research is to develop a specific immune unresponsiveness to alloantigen. Oral administration of antigen prior to systemic challenge has been demonstrated to suppress systemic immune responses, and this antigen specific suppression is termed oral tolerance. This thesis assesses whether oral tolerance can be used to prolong kidney allograft survival and investigates the mechanisms by which this survival is prolonged.
It was found that oral administration of allogeneic splenocytes prior to kidney allograft transplantation dramatically prolonged allograft survival in rats in an allospecific manner. Preservation of structural elements could be observed in kidneys transplanted into fed animals long after control transplants were destroyed. In mixed lymphocytes reaction experiments, splenocytes from fed and kidney transplanted animals exhibited increased, rather than decreased cell proliferation comparing to unfed control, confirming that prolongation of the kidney allografts was not due to a masking of allorecognition but to immunomodulation of the immune response.
To assess the immune response in the kidney allograft, graft infiltrating cells (GIC) were isolated day-5 post transplant and extensively studied. It was found that decreased numbers of GIC were present in the allografts taken from fed animals compared to unfed controls. The decreased number of GIC is mirrored by a decreased number of T cells, especially CD4+ T cells, in the GIC population. The number of CD8+ GIC T cells was similar in both fed animals and controls. To investigate whether CD8+ T cells were allo-active CTL, expression of killer mediators and CTL activity of CD8+ GIC were examined. These CD8+ GIC from fed animals transcribed substantial levels of perforin, granzyme and FasL mRNA and exhibited higher allo-CTL activity than CD8+ GIC from control unfed recipients, suggesting the presence of mature allo-CTL in the graft in fed animals. CD8+ GIC from fed animals also exhibited high levels of IL-4 mRNA, suggesting a Tc2 type regulatory cells. These data are consistent with a hypothesis that CD8+ GIC are regulatory cells that mediate oral transplantation tolerance. To confirm this, adoptive transfer experiments were performed. Prolongation of graft survival could be transferred from rats orally exposed to alloantigen, to naive animals by transfer of CD8+ GIC. These data confirm that intragraft CD8+ T cells are indeed regulatory cells that mediate oral transplantation tolerance. In addition to GIC, it was also demonstrated that regulatory cells are present in spleen and MLN by adoptive transfer of cells from spleen and MLN.
These studies suggest that oral exposure to alloantigen induce the generation of intragraft CD8+ regulatory cells which prolong allograft survival by shifting immune responses toward to type 2 responses and/or by deleting alloreactive T lymphocytes through Fas/FasL interaction.
Thesis (Ph.D.)--Dalhousie University (Canada), 2001.
It was found that oral administration of allogeneic splenocytes prior to kidney allograft transplantation dramatically prolonged allograft survival in rats in an allospecific manner. Preservation of structural elements could be observed in kidneys transplanted into fed animals long after control transplants were destroyed. In mixed lymphocytes reaction experiments, splenocytes from fed and kidney transplanted animals exhibited increased, rather than decreased cell proliferation comparing to unfed control, confirming that prolongation of the kidney allografts was not due to a masking of allorecognition but to immunomodulation of the immune response.
To assess the immune response in the kidney allograft, graft infiltrating cells (GIC) were isolated day-5 post transplant and extensively studied. It was found that decreased numbers of GIC were present in the allografts taken from fed animals compared to unfed controls. The decreased number of GIC is mirrored by a decreased number of T cells, especially CD4+ T cells, in the GIC population. The number of CD8+ GIC T cells was similar in both fed animals and controls. To investigate whether CD8+ T cells were allo-active CTL, expression of killer mediators and CTL activity of CD8+ GIC were examined. These CD8+ GIC from fed animals transcribed substantial levels of perforin, granzyme and FasL mRNA and exhibited higher allo-CTL activity than CD8+ GIC from control unfed recipients, suggesting the presence of mature allo-CTL in the graft in fed animals. CD8+ GIC from fed animals also exhibited high levels of IL-4 mRNA, suggesting a Tc2 type regulatory cells. These data are consistent with a hypothesis that CD8+ GIC are regulatory cells that mediate oral transplantation tolerance. To confirm this, adoptive transfer experiments were performed. Prolongation of graft survival could be transferred from rats orally exposed to alloantigen, to naive animals by transfer of CD8+ GIC. These data confirm that intragraft CD8+ T cells are indeed regulatory cells that mediate oral transplantation tolerance. In addition to GIC, it was also demonstrated that regulatory cells are present in spleen and MLN by adoptive transfer of cells from spleen and MLN.
These studies suggest that oral exposure to alloantigen induce the generation of intragraft CD8+ regulatory cells which prolong allograft survival by shifting immune responses toward to type 2 responses and/or by deleting alloreactive T lymphocytes through Fas/FasL interaction.
Thesis (Ph.D.)--Dalhousie University (Canada), 2001.
Keywords
Health Sciences, Medicine and Surgery., Health Sciences, Immunology.