Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model.
BACKGROUND
PG490-88, a semisynthetic derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium wilfordii Hook F), is effective in prevention of murine graft-versus-host disease (GVHD).


METHODS
PG490-88 was administrated into recipients in a model (B10.D2 [H2d, Mls-2b, Mls-3b]-->BALB/c [H2d, Mls-2a, Mls-3a]) of lethal GVHD. Tolerance was evaluated by transplantation of neonatal hearts. The mechanisms of tolerance were studied.


RESULTS
Host-specific tolerance was established in PG490-88-treated BALB/c recipients. Significant numbers of host reactive Vbeta3+ T cells (3.56+/-1.66% among CD4, 4.06+/-1.62% among CD8, P<0.0001 vs. normal BALB/c mice, P>0.05 vs. normal B10.D2 mice) were present in PG490-88-treated mice, suggesting that clonal deletion was not responsible for the observed tolerance. Spleen cells from PG490-88-treated mice could not respond to the host antigens measured by a popliteal lymph node weight gain assay. The unresponsiveness was unable to be overcome by supplementation of exogenous interleukin (IL)-2. Tolerant Vbeta3+ T cells obtained from PG490-88-treated mice proliferated normally to nonantigen-specific T cell receptor cross-linking. Neither antigen-specific nor nonantigen-specific suppressor cells were found in PG490-88-treated mice. The tolerant mice produced IL-4 rather than IL-2 and interferon (IFN)-gamma.


CONCLUSIONS
Host-specific tolerance induced by PG490-88 in a murine bone marrow transplantation model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 seems to lead to allogeneic tolerance either through the induction of a state of antigen-specific anergy of the responding T cells or through the induction of T-helper cell, type II (TH2) responses.
Chen
Benny J
BJ
Bone Marrow Transplantation Program, Duke University Medical Center, 2400 Pratt Street, Suite 1100, Durham, NC 27705, USA.
Chen
Yanfei
Y
Cui
Xiuyu
X
Fidler
John M
JM
Chao
Nelson J
NJ
D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000382:microbiology; D016207:Cytokines / Q000032:analysis; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009929:Organ Size; D008517:Phytotherapy; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology
D016207:Cytokines; D004224:Diterpenes; D007166:Immunosuppressive Agents; C417603:omtriptolide