Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent.
BACKGROUND
Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected.


METHODS
Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy.


RESULTS
Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue.


CONCLUSIONS
This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.
Papeta
Natalia
N
Infectious Diseases Medicine Division and Partner AIDS Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
Chen
Tao
T
Vianello
Fabrizio
F
Gererty
Lyle
L
Malik
Ashish
A
Mok
Ying-Ting
YT
Tharp
William G
WG
Bagley
Jessamyn
J
Zhao
Guiling
G
Stevceva
Liljana
L
Yoon
Victor
V
Sykes
Megan
M
Sachs
David
D
Iacomini
John
J
Poznansky
Mark C
MC
D000818:Animals; D001681:Biological Assay; D016923:Cell Death; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005818:Genetic Engineering; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D013997:Time Factors
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D007518:Isoantibodies