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The Use of Fluorescent Target Arrays for Assessment of T Cell Responses In vivo
Published on: June 19, 2014
CTLA-4.FasL inhibits allogeneic responses in vivo
M Dranitzki-Elhalel1, J-H Huang, J Rachmilewitz
1Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. michalelhalel@gmail.com
Abstract:
CTLA-4.Fas ligand (CTLA-4.FasL), a paradigmatic 'trans signal converter protein (TSCP)', can attach to APC (via CTLA-4 binding to B7) and direct intercellular inhibitory signals to responding T cells (via FasL binding to Fas receptor), converting an activating APC-to-T cell signal into an inhibitory one. Our previous studies established that CTLA-4.FasL inhibits human primary mixed lymphocyte reactions (MLR) and induces alloantigen-specific hyporesponsiveness ex vivo. The present study extends this to an in vivo context. Using splenocytes from MHC-mismatched C57BL/6 and Balb/c mice, we demonstrated that his(6)CTLA-4.FasL, effectively inhibits murine MLR. Moving in vivo, we demonstrated that subcutaneously administered his(6)CTLA-4.FasL modulates the in vivo response of infused allogeneic splenocytes. his(6)CTLA-4.FasL reduces the number of cells in each cell division, and increases the percentage of dead cells in each division. These findings are consistent with an antigen-induced cell death of the alloreactive cells, and bolsters recombinant TCSP promise as a therapeutic for transplantation diseases.
Insights
CTLA-4.FasL protein converts activating signals into inhibitory ones, suppressing immune responses. This study shows CTLA-4.FasL effectively inhibits immune reactions in vivo, supporting its therapeutic potential for transplantation.
Area of Science:
- Immunology
- Molecular Biology
- Transplantation Science
Background:
- CTLA-4.FasL is a trans signal converter protein (TSCP) that inhibits T cell responses by binding APCs and T cells.
- Previous studies showed CTLA-4.FasL inhibits human mixed lymphocyte reactions (MLR) ex vivo.
- This study investigates the in vivo efficacy of CTLA-4.FasL.
Purpose of the Study:
- To evaluate the in vivo effectiveness of CTLA-4.FasL in a murine transplantation model.
- To assess the impact of CTLA-4.FasL on allogeneic splenocyte responses in vivo.
- To support the therapeutic potential of recombinant TSCPs for transplantation.
Main Methods:
- Used MHC-mismatched C57BL/6 and Balb/c mouse splenocytes for in vitro MLR inhibition assays.
- Administered his(6)CTLA-4.FasL subcutaneously in vivo.
- Analyzed the effects on infused allogeneic splenocytes, including cell division and cell death.
Main Results:
- his(6)CTLA-4.FasL effectively inhibited murine MLR in vitro.
- Subcutaneous administration of his(6)CTLA-4.FasL modulated the in vivo response of allogeneic splenocytes.
- Observed reduced cell numbers and increased cell death in allogeneic splenocytes, consistent with antigen-induced cell death.
Conclusions:
- CTLA-4.FasL demonstrates efficacy in inhibiting immune responses in vivo.
- The findings support the potential of CTLA-4.FasL as a therapeutic agent for transplantation.
- Recombinant TSCPs show promise for treating transplantation-related diseases.
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