Combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses.

Abstract

BACKGROUND:

Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection crossreact with donor antigens. Because of their diminished requirements for costimulation during recall, these pathogen-elicited allocrossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy.

METHODS:

We used an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor.

RESULTS:

We demonstrate that coupling the integrin antagonist anti-leukocyte functional antigen (LFA)-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP³⁺ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone.

CONCLUSIONS:

As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials.

• Authors: William H Kitchens, Divya Haridas, Maylene E Wagener, Mingqing Song, Mandy L Ford
• Journal: Transplantation (Transplantation) Vol. 93 Issue 10 Pg. 997-1005 (May 27 2012) ISSN: 1534-6080 [Electronic] United States
• PMID: 22475765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• B7 Antigens
• CD40 Antigens
• Lymphocyte Function-Associated Antigen-1
• CD40 Ligand

Topics

• Animals
• B7 Antigens (antagonists & inhibitors)
• Bone Marrow Transplantation (immunology)
• CD40 Antigens (antagonists & inhibitors)
• CD40 Ligand (antagonists & inhibitors)
• Graft Rejection (prevention & control)
• Graft Survival
• Humans
• Immunologic Memory
• Lymph Nodes (immunology)
• Lymphocyte Activation
• Lymphocyte Function-Associated Antigen-1 (physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Skin Transplantation (immunology)
• Transplantation, Homologous