Awareness of donor alloantigens in antiadhesion therapy induces antigen-specific unresponsiveness to islet allografts.
BACKGROUND
Antiadhesion therapy using monoclonal antibodies (mAbs) to adhesion molecules in vivo has been shown to produce significant prolongation of graft survival in various transplantation models. However, it remains unclear whether antiadhesion therapy operates by merely blocking adhesion between antigen-presenting cells and T cells physically and/or by blocking costimulatory signals while preserving signals mediated through T-cell receptors in vivo. We examined antigen-specific T-cell responses during and after antiadhesion therapy.


METHODS
BALB/c islets were transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 mice given anti-lymphocyte function-associated antigen (LFA)-1 and/or anti-intercellular adhesion molecule-1 mAb treatment. The animals bearing surviving islet allografts were challenged with BALB/c or third-party islets on day 7 or more than 100 days after transplantation.


RESULTS
Islet allografts were acutely rejected in untreated animals, with a mean survival time (MST) of 19+/-8 days. Administration of anti-LFA-1 mAb induced significant prolongation of graft survival with a mean survival time of 72+/-33 days, and half of the allografts showed indefinite survival. The animals given anti-LFA-1 mAb alone 7 days before transplantation showed acute rejection of BALB/c islets, whereas a significant number of animals given anti-LFA-1 mAb and the BALB/c islet allograft simultaneously accepted secondary BALB/c islets, but rejected third-party islets. Likewise, most of the animals bearing long-term functioning BALB/c allografts for more than 100 days accepted secondary BALB/c islets, but rejected C3H islets acutely. Interestingly, the spleen cells from these animals transferred unresponsiveness to BALB/c islets into the 2.5-Gy x-irradiated recipients, whereas those from naive animals induced acute rejection.


CONCLUSIONS
These results indicate that anti-LFA-1 mAb treatment prevents T-cell activation leading to rejection, but results in a T-cell receptor engagement leading to antigen-specific unresponsiveness maintained by transferrable suppressor cells.
Nishihara
M
M
Department of Surgery II, Osaka University Medical School, Suita, Japan.
Gotoh
M
M
Ohzato
H
H
Ohta
Y
Y
Luo
Z
Z
Dono
K
K
Umeshita
K
K
Sakon
M
M
Monden
M
M
Yagita
H
H
Okumura
K
K
Miyasaka
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D006085:Graft Survival / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007519:Isoantigens / Q000032:analysis*; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012086:Reoperation; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007519:Isoantigens; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1