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Updated: Jul 8, 2026
Murine Full-thickness Skin Transplantation
Published on: January 2, 2017
Survival of skin allografts is prolonged in mice with a dominant-negative H-Ras
Naoko Funeshima-Fuji1, Masayuki Fujino, Hiromitsu Kimura
1Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Abstract:
Ras is a guanine nucleotide-binding protein that plays a major role in regulating the proliferation of T cells. To investigate the mechanism of the Ras/mitogen-activated protein kinase pathway, one of the downstream signal-transduction pathways of T-cell receptors, in the response to alloantigen, we performed full-thickness skin grafting in the major histocompatibility complex (MHC) incompatible strain BALB/c (H-2Kd) (donor) and T-cell-specific H-Ras dominant-negative (dnRas) transgenic (tg) C57BL/6 (H-2Kb) (recipient) male mice. In vitro and in vivo dnRas tg mouse T-cell proliferation and cytotoxic T lymphocyte (CTL) activity assay were also performed. The median graft survival time in control B6/wild type (wt) mouse allografts was seven days. Conversely, the dnRas tg mouse group exhibited a significant (p<0.01) prolongation of graft survival to 15 days. However, all grafts were eventually rejected after one month. Mixed lymphocyte reaction and popliteal lymph node assay revealed that T-cell proliferation was decreased in response to alloantigen, but CTL activity was not changed in the dnRas tg mice. These results suggested that Ras is essential for peripheral T lymphocytes to respond to allo-MHC antigens, and Ras may be a molecular target for controlling transplant rejection.
Insights
Ras protein is crucial for T-cell proliferation in transplant rejection. Inhibiting Ras signaling in T cells prolonged skin graft survival, suggesting Ras as a target for controlling rejection.
Area of Science:
- Immunology
- Molecular Biology
- Transplantation Science
Background:
- Ras proteins are key regulators of T-cell proliferation and signaling pathways.
- The Ras/mitogen-activated protein kinase pathway is a critical downstream signaling cascade of T-cell receptors.
- Understanding these pathways is vital for managing immune responses in transplantation.
Purpose of the Study:
- To investigate the role of the Ras/mitogen-activated protein kinase pathway in T-cell response to alloantigens.
- To determine the effect of inhibiting Ras signaling on T-cell proliferation and graft survival in a mouse model.
Main Methods:
- Full-thickness skin grafting was performed between MHC-incompatible mouse strains.
- T-cell-specific H-Ras dominant-negative (dnRas) transgenic mice were used as recipients.
- In vitro and in vivo assays measured T-cell proliferation and cytotoxic T lymphocyte (CTL) activity.
Main Results:
- dnRas transgenic mice showed significantly prolonged median graft survival (15 days) compared to wild-type controls (7 days).
- T-cell proliferation in response to alloantigen was decreased in dnRas transgenic mice.
- Cytotoxic T lymphocyte (CTL) activity remained unchanged in dnRas transgenic mice.
Conclusions:
- Ras signaling is essential for peripheral T lymphocytes to respond to allo-MHC antigens.
- Inhibition of Ras may serve as a molecular target for modulating T-cell responses and controlling transplant rejection.
