Biological activities of deoxyspergualin in autoimmune disease mice.

Abstract

An assessment of the prophylactic and ameliorative effects of deoxyspergualin (NKT-01), an immunosuppressive agent, was carried out in male MRL/MpJ-lpr/lpr (MRL/1) mice which spontaneously develop lupus-like lesions. When NKT-01 was administered ip daily from the age of either 8 or 19 weeks, diseases such as massive lymphadenopathy, circulating anti-DNA antibody and lupus nephritis were markedly suppressed. The primary response to lipopolysaccharide was significantly reduced in MRL/1mice administered NKT-01but the response to sheep red blood cells was not affected. The ability of spleen cells to release interleukins 2 and 3 with or without mitogen was significantly enhanced in mice receiving NKT-01.These findings demonstrate that NKT-01has therapeutic activity against the development of spontaneous disease in MRL/1 mice. 1253Deoxyspergualin (NKT-01) is a derivative of spergualin, a metabolite of Bacillus laterosporusD shown to have immunosuppressive activities in rodents2). This derivative, with a molecular weight of 496.9 and a moiety bearing a spermidine and a guanidinic group, has been found to suppress antibody production and delayed-type hypersensitivity to sheep red blood cells (SRBC) and to have a stronger activity than spergualin in inhibiting the rejection of skin allografts in rats3). In mice, NKT-01 inhibits the development of graft-versus-host disease43. In rats, NKT-01 inhibits the rejection of heart5), liver6), kidney7) and pancreas8) allografts. The purpose of the present study is to examine whether NKT-01can prevent the spontaneous development of autoimmune disease and affect the immune response, when administered to male MRL/MpJ-lpr/lpr (MRL/1) mice. Materials and Methods AnimalsMale MRL/1and MRL/MpJ-+/-f (MRL/+) mice were purchased from Jackson Laboratories, Bar Harbor, U.S.A. Treatment NKT-01 was supplied by Takara Shuzo Co., Ltd., dissolved in saline and sterilized by passing through a 0.22-/mi filter. In a previous experiment, when NKT-01was administered ip daily at an immunosuppressive dose of 3 mg/kg from week 12, weight loss was observed about 6 weeks after the initial administration of NKT-01. Therefore, the dose was lowered to 1.5 mg/kg in all experiments.

15-deoxyspergualin prevents mucosal injury by inhibiting production of TNF-α and down-regulating expression of MD-1 in a murine model of TNBS-induced colitis

“…In agreement with these experimental observations, clinical studies in human have demonstrated that DSG reverse kidney [32,33] and liver [34] allograft rejection. Also, DSG has been effective in decreasing the severity of autoimmune diseases and GVHD [35,36]. However, in spite of these numerous studies, the precise mechanism of action of DSG is unsettled.…”

Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine Moiety

“…Since its discovery, DSG has been widely studied and demonstrated efficacy first as an anticancer agent, then in animal transplantation either in allografts or xenografts, and more recently in graft-versus-host disease (GVHD) animal models . DSG has also been widely investigated in autoimmune diseases. The high potential of DSG to reverse renal graft rejection was first reported in 1990 .…”

Synergistic effect of donor-specific blood transfusion and a short course of deoxyspergualin in rat kidney transplantation

“…If the autopsy disclosed abnormal findings such as hydronephrosis and infection, the animal was excluded from the experimental group. Deoxyspergualin (DSG), an analogue of spergualin, is produced as a metabolite by Bacillus laterosporus [18] and has been confirmed to have a strong immunosuppressive effect in various transplantation models including mice [15], rats [23], dogs [l], monkeys [4], and humans [2]. The mechanism of action of DSG has not been clarified yet, but some reports have shown that DSG has a totally different mechanism of action [5] than newly developed, potent immunosuppressive drugs such as cyclosporin (CyA) [7], FK 506 [20], or OKT3 monoclonal antibody [3].…”