Strategies to induce marked prolongation of secondary skin allograft survival in alloantigen-primed mice.
Alloreactive memory T cells mediate accelerated rejection. We investigated the effect of polyclonal anti-T-cell antibody (ALS) and rapamycin (RAPA) on skin allograft survival in naïve or alloantigen-primed mice. ALS prolonged graft survival in both naïve and alloantigen-primed mice. T-cell depletion by ALS was associated with increased CD4(+)CD44(hi)OX40(+) and CD8(+)CD44(hi)CD122(+) memory T cells. Addition of RAPA to ALS extended graft survival in naïve mice, but had no effect on secondary allograft survival in alloantigen-primed mice. In adoptive transfer experiments, RAPA inhibited alloantigen-stimulated proliferation and allograft rejection by naïve T cells. In contrast, alloantigen-primed memory T cells, particularly CD4(+)CD44(hi)OX40(+) and CD8(+)CD44(hi)CD122(+) T cells, were resistant to RAPA in response to alloantigen and mediated accelerated rejection in the presence of RAPA. Resistance to RAPA by alloantigen-primed mice was overcome by the use of high-dose ALS, which achieved marked prolongation of secondary skin allograft survival (>100 days). Inhibition of CD122(+) T cells and/or OX40/OX40L costimulation blockade, combined with low-dose ALS and RAPA, was also effective. These results demonstrate that tolerance may be achieved in allosensitized individuals by T-cell depletion- and RAPA-based strategies employing high-dose ALS or targeting CD122(+)CD8(+) T cells and/or the OX40/OX40L costimulatory pathway.
Minamimura
K
K
The Transplant Center, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Sato
K
K
Yagita
H
H
Tanaka
T
T
Arii
S
S
Maki
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D007156:Immunologic Memory; D007518:Isoantibodies / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D023421:Models, Animal; D020123:Sirolimus / Q000627:therapeutic use; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D007518:Isoantibodies; D020123:Sirolimus