Table 1. The preclinical pharmacological study of triptolide and PG490-88/F60008 against autoimmune diseases and transplantation rejection.

Compounds	Disease	Models	Regimens	Reported responses	Possible mechanism	Refs
Triptolide	Rheumatoid arthritis	Type II collagen-induced arthritis (CIA) in Lewis rats	Oral administration of 0.1 mg·kg−1·d−1 for 28 d	Significant delay in time to onset of arthritis, as well as significantly decreased arthritis incidence, clinical arthritis severity score, histopathological arthritis severity score, and in vivo cell-mediated immunity to collagen	Suppressed cell-mediated immune responses	16
	Rheumatoid arthritis	Collagen-induced arthritis in DBA/1 mice	Oral administration (8, 16, and 32 μg·kg−1·d−1, started when the first clinical signs of disease were beginning, and continued for 21 d	Arthritis incidence was reduced in all groups after receiving triptolide (8–32 μg/kg), arthritis scores was suppressed at 16 and 32 μg/kg doses	Suppression of MMPs, up-regulation of TIMPs, interference with the gene expression of proinflammatory cytokines and PGE2 production, inhibition of NF-κB	44
	Arthritis	Adjuvant-induced arthritis in rat	ip administrations from day 14–20 after immunization at a dose of 0.1, 0.2, and 0.4 mg·kg−1·d−1	Thickness index decreased in all administration groups and maximal inhibition occurred at a dose of 0.4 mg/kg	Over-expression of MCP−1, MIP−1α, and RANTES at both mRNA and protein levels were inhibited	45
	GVHD	C57BL/6 to BDF1 murine BMT model	Oral or intraperitoneal treatment for only 14 d	Prevented GVHD induction and development, produced long-term survival	Induction of anergy and a deviation away from a proinflammatory phenotype	52
	Transplantation	F344 donor to Lewis recipient rat cardiac transplantation	Intraperitoneal treatment at doses of 0.04, 0.08, 0.16, and 0.32 mg·kg−1·d−1 starting on the day of transplantation	The median survival time (MST) was 8 d for placebo; 9.5, 11, 14, and 19 d for triptolide monotherapy at doses of 0.04, 0.08, 0.16, and 0.32 mg·kg−1·d−1, respectively,	/	46
	Transplantation	Mouse model of cardiac transplantation	ip administration of 3 mg·kg−1·d−1 of triptolide at d 0–7, 9, 11, 13, and 15 post transplantation 0.1 mg·kg−1·d−1	MST in vehicle group: 7.66±0.8 d, in triptolide group: 23.5±5.3 d	/	47
	Transplantation	Skin allograft rejection		Prolonged the graft survival when triptolide was given for 9 d after transplantation, but not before transplantation.	Inhibits lymphocyte activation at a relatively late stage	49
	Transplantation	Rat cardiac and renal allograft (from Brown Norway into the abdomen of Lewis rats)	ip dosing of 2.5, 5, 10, 20, or 30 mg·kg−1·d−1 for 16 d; oral administration for 16 d at doses of 5, 10, or 30 mg·kg−1·d−1 starting 1 d before transplantation	MST of heart allografts was significantly longer in ip dosing of 10, 20, or 30 mg·kg−1·d−1, also in oral administration at doses of 5, 10, or 30 mg·kg−1·d−1 MSTs of renal allograft in ip dosing of 20, 30 mg·kg−1·d−1 significantly longer	/	55
PG490-88 (F60008)	GVHD	Bone marrow and spleen cells transplantation (B10. D2 to BALB/c mice)	ip at 0.535 mg·kg−1·d−1 for the first 3 weeks after transplantation	Protected from developing GVHD up to 100 d	Inhibition of alloreactive T cell expansion through interleukin-2 production	59
	Transplantation	MHC-mismatched renal transplanted into cynomolgus monkeys	0.03 mg·kg−1·d−1 by gavage	PG490-88 monotherapy failed to prolong allograft survival	Inhibition of T-cell activation and a decrease in IFN-? production and NF-AT/NF-κB activity	61
	Transplantation	Dog renal transplantation model	Oral administration at 0.06 mg·kg−1·d−1	Prolonged graft survival from a MST of 6 d to 11 d	Inhibition of complement activation and T-cell infiltration	62
	Transplantation	Chronic rejection in rat kidney (F344 to LEW rats)	0.5 mg·kg−1·d−1 for 10 d	Moderate histological changes on d 90	Suppression of intragraft gene expression	63
	Transplantation	Acute renal rejection across the ACI-to-LEW rat strain	Orally administered at 0.3, 0.5, or 1.0 mg·kg−1·d−1d for 10 d	Dose-dependent prolongation of kidney allograft survival at 0.5 and 1.0 mg·kg−1·d−1	/	64
	Transplantation	Mouse heterotopic tracheal allograft model of obliterative airway disease	Intraperitoneal injection at 0.25 mg·kg−1·d−1	Attenuates airway obliteration and inhibits accumulation of inflammatory cells	Direct effect on DC or an indirect effect resulting from increased T-cell-mediated apoptosis to be elucidated	65
	GVHD	Murine allogeneic BMT model (B10.D2 to BALB/c)	ip administration at 0.0535 mg/mL daily for the first 3 weeks after BMT	Protected from lethal GVHD for more than 100 d	Induction of responding T cells anergy or TH2 responses	59,66
	Lung fibrosis	Bleomycin-induced lung ip administered at 0.25 mg/kg on	the same day or 5 d after bleomycin installationfibrosis	Blocks both inflammation and fibrosis in the bleomycin model of mouse lung fibrosis	Inhibition in TGF-β gene expression	67