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PubMed2005

FK778, a novel immunosuppressive agent, reduces early adhesion molecule up-regulation and prolongs cardiac allograft survival.

The adhesion molecules, P-selectin, ICAM-1, and VCAM-1 are important mediators of T-cell adhesion and T-cell co-stimulation. We investigated the effect of the malononitrilamide FK778 on cardiac allograft survival, acute allograft rejection, and adhesion molecule up-regulation in a heterotopic, cardiac transplantation model. Rats received low- or high-dose FK778 or no treatment. Grafts were harvested on the fifth postoperative day for histologic examinations. To assess allograft survival, recipients were treated for a maximum of 10 days and grafts were harvested after cessation of the contractile activity. FK778 low dose showed a mild but significant decrease in mononuclear infiltration but failed to markedly reduce histologic rejection, adhesion molecule up-regulation, or to prolong allograft survival. However, high-dose FK778 treatment significantly reduced early up-regulation of P-selectin, ICAM-1, and VCAM-1, abolished infiltration, reduced histologic rejection and resulted in prolonged cardiac allograft survival. Therefore, FK778 is a novel, highly desirable immunosuppressive drug for transplantation medicine.

Acute Disease↗

PubMed1992

A comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro.

The agents cyclosporine, tetranactin (TN), and didemnin B (DB) were compared for their ability to inhibit proliferative human T cell responses in vitro, using anti-CD3, PHA, alloantigen, or tetanus toxoid as stimuli and using monocytes or Langerhans cells as antigen-presenting cells/accessory cells (APC/AC). We found that all three agents suppressed T cell activation in a dose-dependent fashion, irrespective of the stimulus of APC/AC type used. Both T cells and APC/AC were affected by the drugs. DB appeared to be the most potent suppressive drug (IC50 = 1-4 ng/ml), whereas CsA and TN exerted approximately similar potency (IC50 = 50-60 ng/ml). Remarkably however, DB was toxic at a concentration of 10 ng/ml, which is quite close to the inhibition-inducing dose. No toxicity was observed with CsA and TN at doses up to 5000 ng/ml. The agents TN and DB could interrupt ongoing T cell responses and could block responsiveness to exogenous recombinant IL-2. Expression of IL-2 receptors was slightly inhibited by all three drugs. Expression of MHC class II molecule HLA-D and of adhesion molecules LFA-1, LFA-3, and ICAM-1 was clearly reduced by DB, giving an explanation for the observed inhibition of cluster formation between T cells and APC/AC. Except for a slight reduction of LFA-3 by TN, CsA and TN did not affect the expression of any of these cell surface markers or the formation of clusters. Differences in the effects of CsA, TN, and DB on immune responses in vitro and on the phenotype of T cells and APC/AC suggest that these immunosuppressive drugs have different inhibitory mechanisms.

Cell Survival↗

PubMed2002

[Peliosis hepatis as the cause of liver affection in a patient treated with immunosuppressive agents].

A case of peliosis hepatis in a 64-year-old woman treated with azathioprine because of a lung transplantation is described. The patient was admitted owing to epigastric pain and jaundice. Sixteen months before admission the patient had had a lung transplantation because of pulmonary emphysema. A liver biopsy showed multiple, dilated, blood-filled liver sinusoids consistent with peliosis hepatis. Besides azathioprine, the patient was treated with cyclosporine and prednisolone, but none of these drugs are known to be responsible for the development of peliosis hepatis. This rare condition, which causes liver affection in patients treated with azathioprine, should be kept in mind.

Azathioprine↗

PubMed1981

Selective effects of immunosuppressive agents against the delayed hypersensitivity response and humoral response to sheep red blood cells in mice.

The effects of cyclophosphamide, methotrexate, procarbazine, and azathioprine on the delayed-type hypersensitivity (DTH) response and antibody response to sheep red-blood cells were studied in mice. All the compounds inhibited the antibody response. Using appropriate dosage schedules, cyclophosphamide, methotrexate and procarbazine either potentiated or had no effect on DTH. In contrast, azathioprine inhibited the DTH response as measured 24 h after challenge but potentiated the DTH response measured 48 h after challenge. This system provides a convenient means of searching for drugs with selective effects on either DTH or antibody production.

Animals↗

PubMed1976

Evaluation of carrageenan as an immunosuppressive agent and mediator of intravascular coagulation.

Carrageenan suppressed antibody responses to SRBC in mice and rats, measured in terms of splenic IgM PFC production. The effect, in mice, was dependent on dose and on the temporal relationship between treatment and antigen administration. Carrageenan was found to alter the time course of the PFC response and also to produce disseminated intravascular coagulation. Some correlation between the observed effects and the use of chemically distinct carrageenans was found. The possible mode of action of carrageenan is discussed in the light of these, and other findings.

Animals↗

PubMed1976

Naturally occurring immunosuppressive agents. II. The ability of cell-free liver extracts to modify the rejection of allogeneic skin grafts in the rabbit.

It has been demonstrated that cell-free extracts of pig, rabbit and human liver, but not of other parenchymal organs, contain a factor or factors capable of suppressing the proliferative responses of allogeneic and xenogeneic lymphoid cells stimulated with PHA, PWM, Con-A and allogeneic lymphocytes. Intravenous injection of the liver extract is capable of modifying significantly the skin allograft rejection reaction in normal adult outbred rabbits. Work is now in progress to isolate this factor and to determine its composition.

Animals↗

PubMed1996

[Combined treatment with factor VIII and immunosuppressive agents in a young woman with acquired factor VIII inhibitor].

A twenty seven year-old woman is reported with severe haemorrhagic symptoms caused by an acquired coagulant factor VIII inhibitor eleven months after delivery. The inhibitor was quantified as 77 units according to the Bethesda method. Steroids treatment and high-dose immunoglobulins failed to elicit any response. Combined chemotherapy will cyclophosphamide, vincristine and prednisone after intravenous factor VIII, every fourth week, succeeded in eradicating the acquired inhibitor and progressively restoring the rates of factor VIII in this patient with acquired haemophilia.

Adult↗

PubMed1996

[Manifestation of nasal allergy in ovalbumin-sensitized mice--as compared with mast cell-deficient mice, determined with an immunosuppressive agent].

We performed general and topical sensitization by ovalbumin in wild type, WBBFI6- +/+ (+/+), mice and mast cell-depleted type, WBBFI6-W/Wv (W/W)v, mice. Although both mice showed almost equal PCA liters, W/Wv mice showed a lower level of antigen-induced eosinophilia, and more significant nasal symptoms and histamine hypersensitivity than +/+ mice. Antigen-induced increased levels of histamine and IL-5 in nasal lavage fluid were noted in +/+ mice. Cyclosporin A pre-treatment inhibited the antigen-induced nasal symptoms, nasal eosinophilia and increased levels of histamine and IL-5 in nasal lavage fluid in the +/+ mice. The PCA titer was not affected by the treatment in either kind of mouse.

Animals↗

PubMed1988

Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation.

Transforming growth factor-beta (TGF-beta), a product of neoplastic and hemopoietic cells, is a bifunctional regulator of the immune response. At femtomolar concentrations, TGF-beta stimulates monocyte migration, and picomolar quantities induce synthesis of monocyte growth factors, including IL-1, that may promote tissue repair by regulating fibrosis and angiogenesis. Paradoxically, TGF-beta at picomolar concentrations also blocks the ability of IL-1 to stimulate lymphocyte proliferation. At 0.01 to 1.0 ng/ml, TGF-beta 1 and its homologue, TGF-beta 2, suppress the IL-1-dependent murine thymocyte proliferation assay. TGF-beta also inhibits human peripheral blood T lymphocyte mitogenesis. Inhibition of cell division appears to occur after activation of the lymphocytes inasmuch as neither gene expression nor translation of IL-2R is suppressed. Furthermore, TGF-beta does not block synthesis of IL-2. Therefore, TGF-beta 1 and TGF-beta 2 likely act at a site distal to IL-1 to block lymphocyte DNA synthesis. These findings suggest that TGF-beta secreted in an inflammatory site may be beneficial in diminishing lymphocyte function while promoting fibrosis and tissue repair. However, TGF-beta generated by neoplastic tissues may provide a mechanism for unrestricted tumor cell growth through its selective immunosuppressive effects.

Humans↗

PubMed1997

Glucocorticosteroids as immunosuppressive agents.

When administered at pharmacological dosages, glucocorticosteroid hormones alter leukocyte kinetics, phagocytic cell function, cell-mediated immunity, and, to a lesser extent, humoral immunity. These properties are used to advantage in the treatment of immunologically mediated disease. Corticosteroids are used to suppress pathological immune responses associated with autoimmunity, inhibit rejection of allogenic tissues after organ transplantation, and to diminish inflammation associated with a wide variety of hypersensitivity disorders. The mechanisms by which corticosteroids relieve these conditions are still not completely understood but have recently become more comprehensible. By understanding how corticosteroids exert their effects, we can make better clinical decisions in the management of immune-mediated disease.

Animals↗

PubMed2001

FTY720, a novel immunosuppressive agent, induces apoptosis in human glioma cells.

FTY720, a metabolite from Isaria sinclairii, has been developed to be a potent immunosuppressive drug with induction of apoptosis in T cells and several cell lines. We investigated whether FTY720 induces apoptosis in human glioma cell lines, since they are relatively resistant to multiple apoptotic stimuli. In human glioma cells including T98G, FTY720 induced apoptosiswith ED50 between 1 to 10 microg/ml, while etoposidedid not induce apoptosis at the same doses. Among the caspase family proteases, mainly caspase-6 was activated during the apoptosis by FTY720 but not etoposide. In addition, FTY720 caused tyrosine dephosphorylation of FAK and did not activate a FAK-PI3-kinase survival pathway. This was confirmed also by the observation that orthovanadate prevented FTY720-induced dephosphorylation of FAK and inhibited FTY720-induced cell death. We assumed that FTY720 induced FAK dephosphorylation and cut off the FAK-PI3-kinase pathway resulting in the induction of apoptosis via caspase-6 activation in these glioma cells.

Antineoplastic Agents, Phytogenic↗

PubMed1987

T lymphocyte line-mediated experimental allergic encephalomyelitis--a pharmacologic model for testing of immunosuppressive agents for the treatment of autoimmune central nervous system disease.

An acute form of transferred experimental allergic encephalomyelitis was induced by injection of activated, myelin basic protein-specific T cell line lymphocytes. The course of the disease as a function of the dose of cytotoxic cells was investigated, and the effect of i.p. and i.v. application of methotrexate on mortality and morbidity was determined. Depending on the time of administration, beneficial therapeutic effects could be seen as early as 1 week. Survival of animals that had received a lethal dose of 15 to 20 X 10(6) cells/kg proved to be the most valuable parameter. T lymphocyte line-mediated experimental allergic encephalomyelitis is a predictable acute central nervous system model disease that does not require antigen depots or cell donor animals.

Animals↗

PubMed1971

Effect of an immunosuppressive agent, cyclophosphamide, on chronic lactic dehydrogenase virus viremia of mice.

The immunosuppressive drug cyclophosphamide was used to study the effect of immunosuppression on the degree of chronic lactic dehydrogenase virus (LDV) viremia in mice. Weekly injections of cyclophosphamide caused an increase of LDV viremia of ca. 2.5 log(10) 50% infectious doses per ml as compared to the viremia in the nontreated mice. This increase occurred at about the same time that the formation of antibody with a neutralization index of 2 to 3 log(10) per ml could be demonstrated in the serum of control mice, whereas both neutralizing antibody and sensitized (antibody-bound but infectious) virus were absent in the immunosuppressed mice. In one experiment, antibody did not reappear 28 weeks after a 24-week course of cyclophosphamide treatment. In another experiment in which the drug was given for 12 weeks, antibody appeared again in the treated mice 14 weeks after cessation of drug administration and was accompanied by a decrease in viremia. The normal decrease of early viremia during the first 2 weeks of infection in immunosuppressed mice suggests that the immune response is not the cause of this initial decrease in LDV viremia but that interferon and perhaps other nonimmune factors may be involved here. The increased viremia in the immunosuppressed mice during the later stages of infection indicates that the immune response plays an important role in partial control of chronic viremia. The quantitative correlation between the decrease in neutralizing antibody and the increase in viremia in immunosuppressed mice suggests that antibody rather than cellular immunity may be the more important immune factor in the control of chronic viremia.

Animals↗

PubMed1998

[Mycophenolate mofetil (MMF) for prevention of kidney transplant rejection. A new immunosuppressive agent. International Mycophenolate Mofetil Study Group].

1493 patients were enrolled in 55 centers in Europe, Canada, Australia and the USA comparing the efficacy of mycophenolate mofetil (MMF) in daily doses of 2 and 3 g with placebo/azathioprine (PLA/AZA) for the prevention of acute rejection in renal transplant patients. Acute rejections and graft loss and death at 1 year were measured per trial and these data were combined and analyzed in a pooled fashion. The three pooled treatment groups were well balanced regarding demographic characteristics and cause of renal failure leading to transplantation. At one year the graft survival rate was 90.4% and 89.2% in the MMF 2 g and 3 g groups compared with 87.6% in the PLA/AZA-group. MMF 2 and 3 g were significantly better than PLA/AZA in reducing biopsy proven rejection at one year: 40.8% placebo/aza vs. 19.8% in the MMF 2 g group and 16.5% in the MMF 3 g group.

Adult↗

PubMed2003

Thrombotic thrombocytopenic purpura (TTP): initial treatment with plasma exchange plus steroids and immunosuppressive agents for relapsing cases.

BACKGROUND: The thrombotic thrombocytopenic purpura (TTP) is a rare disorder with a high mortality rate if untreated or delayed therapy. Whether immediate diagnosis and promptly treated with plasma exchange can change the grave prognosis? METHOD: Retrospective analysis was performed on clinical characteristics and treatment outcome of 13 patients diagnosed and treated during a 6-year period, from August 1994 to August 2000, in a tertiary care university hospital in Taiwan. RESULTS: Among the patients, 8 were males and 5 were females, 10 were idiopathic, 2 were ticlopidine, and 1 was SLE-induced; 12 (92.3%) had neurological abnormalities, 11 (84.6%) had ecchymosis, 8 (61.5%) had fever, and 6 (46.2%) had renal impairment (creatinine > or = 1.5 mg/dL) at initial presentation of the syndrome. Excluding the SLE patient, 6 of 10 (60%) had shown antinuclear antibody (ANA) non-specific positive (titer > or = 1:40). All patients were initially treated with plasma exchange plus steroids. Of these 13 patients, 11 (84.6%) achieved complete remission, one had partial remission, and one, which was ticlopidine-induced, had no response and died of a progressive disease complicated with pneumonia. Within a median follow-up period of 31 months, 4 of 11 patients who achieved complete remission relapsed after one week, two weeks, three weeks, and three months, respectively. In the four relapsing patients, three late relapsing patients received FFP infusion, increased steroid dosages, added cyclophosphamide plus vincristine; and one early relapsing patient, relapsing twice, received an additional two courses of plasma exchange and added cyclophosphamide plus vincristine. All of the four patients achieved complete remission again. The patient who had partial remission relapsed early and responded promptly to another course of plasma exchange plus cyclophosphamide and vincristine and achieved complete remission. CONCLUSION: Based on the results in this study, we conclude that plasma exchange plus steroids can effectively treat TTP. For patients with a refractory or relapsing disease, immunosuppressive therapy with cyclophosphamide plus vincristine should be administered as well.

Adolescent↗

PubMed1997

Prolongation of rat islet allograft survival by the immunosuppressive agent leflunomide.

The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2 +/- 0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0 +/- 1.6, 29.8 +/- 3.7, and 29.0 +/- 5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21 +/- 3.5 days. When CsA (5 mg/ kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8 -/+ 4.7 and 36.0 -/+ 6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/ day, MSTs were further increased to 45.8 -/+ 8.8 or 37.4 -/+ 4.7 days, respectively. Graft MST was 56.4 -/+ 9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2 -/+ 0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8 -/+ 1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its immunosuppressive effect was improved when combined with CsA.

Animals↗

PubMed1992

Inhibitors of human purine nucleoside phosphorylase. Synthesis of pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase inhibitors as potentially T-cell selective immunosuppressive agents. Description of 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d] pyrimidin-4-one.

Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme in the purine cascade and has been a target for drug design for sometime. A series of potent human PNP inhibitors, pyrrolo[3,2-d]pyrimidines (9-deazaguanines), has been synthesized and evaluated in the enzyme assay and in the cell line assay using MOLT-4 (T-cell) and MGL-8 (B-cell) lymphoblasts for selectivity. One of the compounds, 2,6-diamino-3,5- dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidine-4-one (11c; CI-972), was found to be moderately potent, competitive, and reversible inhibitor of PNP with Ki = 0.83 microM. It was also found to be selectively cytotoxic to MOLT-4 lymphoblasts (IC50 = 3.0 microM) but not to MGL-8 lymphoblasts and was evaluated further. Compound 11c (CI-972) is under development in the clinic.

B-Lymphocytes↗

PubMedDate not supplied

[Evolution of patients with rheumatoid arthritis treated with immunosuppressive agents between 1965 and 1973].

The authors report the results of a study of 139 of their patients with severe rheumatoid arthritis, treated with chlorambucil of cyclophosphamide between 1965 and December 1973, with an observation period of 4 to 12 years. 8 patients were lost to follow-up, 38 died and 93 were reexamined. In this series 7 deaths were attributed to hemolymphoreticulopathy of various cytological types; 6 deaths were due to visceral cancer and 2 others to cancer of the tonsils. They confirm that such treatments increase the risk of hemopathy but apparently not the risk of visceral cancer. The risk was not a function of the total dose of the drug administered since no neoplasia was observed in the 25 subjects who received the highest doses. The addition of chlorambucil to cyclophosphamide seems to increase the risk of hemopathy. It was noticed that the 7 cases of hemolymphoreticulopathy occured after 60 years.

Adult↗