alpha4 integrin in islet allograft rejection.
BACKGROUND
Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between alpha4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival.


METHODS
Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against alpha4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of alpha4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis.


RESULTS
Treatment with anti-alpha4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-alpha4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, alpha4 integrin+, cytotoxic T cells.


CONCLUSIONS
These data show that alpha4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualitatively affecting either T cell activation or migration to the graft. Conversely, anti-alpha4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between alpha4 integrin and its ligands may provide novel forms of immunosuppression.
Stegall
M D
MD
The Transplantation Research Laboratory, Department of Surgery, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
Dean
P G
PG
Ninova
D
D
Cohen
A J
AJ
Shepard
G M
GM
Gup
C
C
Gill
R G
RG
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism*; D006085:Graft Survival; D007108:Immune Tolerance; D039441:Integrin alpha4; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000494:pharmacology; D012086:Reoperation; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019010:Vascular Cell Adhesion Molecule-1; C076687:CS1 peptide; D039441:Integrin alpha4