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PubMedDate not supplied

[Current trends in the study of immunosuppressive agents].

An analysis has been made of the specificity of the action of immunodepressants with respect to different types of immune responses. The main attention is concentrated on the specificity of the drug action in varied autoimmune diseases. It has been suggested that the general principles of tumor chemotherapy may be applicable to chemotherapy of autoimmune disorders. It is recommended that immunodepressants be studied in experimental autoimmune diseases of man and that optimal regimens of drug administration be developed accordingly.

Adjuvants, Immunologic↗
PubMed2002

Tuberculin-induced lymphocyte proliferation in whole blood: an antigen specific method for assessing immunosuppressive agents.

Antigen-stimulated whole blood cultures have not been used to study the effects of immunosuppressive drugs. The aim of this study was to assess the potential usefulness of tuberculin purified protein derivative (PPD)-stimulated lymphocyte proliferation in whole blood for studying the effects of T cell inhibitory agents. We have investigated whether PPD causes antigen specific T cell proliferation, and the role of the major histocompatibility complex class II (MHC class II), co-stimulation and IL-2 in the development of this response. We have also studied the effects of prednisolone and cyclosporin on lymphocyte proliferation. Heparinised blood from healthy volunteers was diluted in culture medium and incubated with PPD. Cell proliferation, measured by liquid scintillation counting, was maximal using 1000 units/ml PPD incubated in 10% whole blood for 6-7 days. A population of large CD4+ lymphocytes appeared in cultures incubated with PPD, suggesting that the major responding population was composed of T lymphocytes. There was no significant response to the negative control antigen KLH, indicating that proliferation was antigen specific. Monoclonal antibodies (mAbs) against MHC, CD2, CD26, CD28 and IL-2 inhibited proliferation. Prednisolone was more potent than cyclosporin in this assay (IC50 values; prednisolone 20 nmol, cyclosporin 278 nmol). For the first time, this report shows that the PPD causes antigen specific lymphocyte proliferation in whole blood, which is dependent on antigen presentation via MHC class II, co-stimulation and IL-2 production. Because the proliferative response is dependent on the major interactions that lead to T cell activation, this simple assay can be used to assess the effects of novel immunomodulators.

Blood Cells↗
PubMed2003

Mammary gland-specific secretion of biologically active immunosuppressive agent cytotoxic-T-lymphocyte antigen 4 human immunoglobulin fusion protein (CTLA4Ig) in milk by transgenesis.

A major challenge in the field of transplantation is to prevent graft rejection and prolong graft survival. Tolerance induction is a promising way to achieve long-term graft survival without the need for potent immunosuppression and its associated side effects. The recent success of co-stimulatory blockade by the chimeric protein CTLA4Ig in the modulation of the recipient's immune system and the prolongation of graft survival in animal models suggests a possible application of CTLA4Ig in clinical transplantation. To produce sufficient amounts of CTLA4Ig for future clinical application, we sought to use the mammary gland as a bioreactor and produce CTLA4Ig in the milk of transgenic farm animals. Prior to the generation of transgenic farm animals, we tested our strategy in mice. Using the promoter of the sheep beta-lactoglobulin gene, we expressed our CTLA4Ig chimeric gene in the mammary gland of transgenic mice. The yield of CTLA4Ig was fivefold higher in transgenic milk than that from transfected cells. Purified milk-derived CTLA4Ig is biologically active and suppresses T cell activation. We showed that the production of CTLA4Ig in the milk has no adverse immunosuppression effect on the transgenic animals and the offsprings that were fed with the transgenic milk. The findings suggest that the approach to produce CTLA4Ig in milk by transgenesis is feasible; further studies involving farm animals are warranted.

Abatacept↗
PubMed1999

The effect of immunosuppressive agents (FK-506, rapamycin) on renal P450 systems in rat models.

It is well known that cyclosporin, rapamycin and FK-506 (tacrolimus) are metabolized by the liver microsomal cytochrome P450 enzyme system. Although there have been reports of interaction between these drugs and the renal P450 enzyme system, differences among these immunosuppressants has not been comprehensively demonstrated. We have studied the individual capacities of these immunosuppressants to induce renal microsomal P450 enzymes similar to CYP2B4 and CYP4A2 by examining renal function in treated rats, and have correlated the results by means of biochemical, immunological and immunohistochemical assays of renal P450 enzymes. Cyclosporin caused impairment of renal function with an increase in renal-specific P450 content, but FK-506 and rapamycin did not. Laurate omega- and (omega-1)-hydroxylase activity increased in rats treated with rapamycin but decreased in those treated with FK-506. Prostaglandin A1 (PGA1) omega-hydroxylase activity increased in rats treated with FK-506 but was reduced by treatment with cyclosporin. Aminopyrine N-demethylase activity increased in rats treated with cyclosporin or FK-506, but not in those treated with rapamycin. Western-blot analysis revealed significant induction of P450, (similar to CYP2B4 of the rabbit P450 isozyme) in kidneys from rats treated with cyclosporin but not in those from rats receiving FK-506 or rapamycin. Histochemical studies clearly demonstrated a form of P450 such as CYP4A2 in the proximal tubules of rats treated with cyclosporin, but not in those of rats treated with FK-506 or rapamycin. These results show that although cyclosporin has a strong effect on renal P450 systems and induces such a system in kidney cortex (microsomal P450), FK-506 and rapamycin have no substantial effect on the induction of renal P450. These findings might clarify the nephrotoxicity induced by these immunosuppressive drugs.

Aminopyrine N-Demethylase↗