Immunosuppressive peptides in clinical practice

Immunosuppressives are those agents that reduce the efficacy or activity of a body’s immune response system. In general, the term immunosuppression refers to reduction in the activation of immune response. Immunodeficiency refers to increased risk for infection. The immune system has the ability to detect and eliminate foreign pathogens and tumor cells from the body. In individuals with auto immune disorder, the immune system does not distinguish with healthy tissues and antigens, and the body will sets off a reaction that can destroy normal tissues.

Autoimmunity is associated with defective functioning of T cell signaling. Several medications are available for suppressing over-reactive T lymphocytes and treatment using these medications can cause life threatening side effects. The exact cause of autoimmune disease is still unknown, but several factors have been identified to play a key role in initiating the condition such as genetics, environment, gender and malfunctioning lymphocytes.

Autoimmune disease cannot be considered as a congenital disease; it can be due to infection, when certain bacterial protein evokes the immune response. Immunosuppressive agents are used for the treatment of auto-immuno diseases and organ transplantation. After organ transplantation, the body has the tendency to reject the new organ- due to differences in human leukocyte antigen haplotypes between the recipient and the donor. The immune system detects the new organ as hostile and attempts to remove it by attacking it with recipient leukocytes thereby destroying the tissue. Immunosuppressant drugs are used as a counter measure to suppress the hyperactive component of the immune system. A major side effect in using immunosuppressant is that the body becomes vulnerable to infections and malignancy. Immunosuppression can be induced deliberately or non-deliberately. The deliberate method of inducing immunosuppression is via immunosuppressive drugs or immunosuppressant. These drugs have the ability to target only hyperactive components of the immune system and do not cause any significant immunodeficiency. In spite of its immunosuppressive activity, all class of drugs have the potential to cause immunodeficiency. In case of non-deliberate immunosuppression the suppressive activity can be caused by aging, malnutrition and due to chronic infections such as HIV. One of the main side effects in non-deliberate immunosuppression is immunodeficiency, which result in increased susceptibility to pathogens such as bacteria and virus.

The most common and one of the oldest immunosuppressive drugs used are glucocorticoids. They act by inhibiting secretion of inflammatory cytokines there by supporting the activation of anti-inflammatory signaling cascade. The most common member in this family is cortisone. Vitamin D is also used as an immunosuppressive agent. The physiologically active form of Vitamin D calcitriol, show immunosuppressive properties and is used in supplementation therapy for the treatment of multiple sclerosis. The immunosuppressive drugs can be classified into glucocorticoids, antibodies, cytostatics, drugs acting on immunophilins and other drugs. The drugs coming under this class can suppress allergic, inflammatory and autoimmune disorders.  The cytostatics include alkylating agents and anti- metabolites. In case of antibodies, polyclonal antibodies, T-cell receptor directed antibodies, IL-2 receptor directed antibodies and monoclonal antibodies are used as immunosuppressants. The drugs acting on immunophilins as immunosuppressants include ciclosporin, sirolimus and tacrolimus. Other drugs used as immunosuppressant are TNF binding proteins, small biological agents such as Fingolimod (currently in phase 3 clinical trial) and Myriocin, mycophenolate, interferons and opioids. Several immune suppressive agents are used for treating over reactive immune system with different mechanism of action. Most of the drugs initiate action by targeting the gene expression, specific kinases and phosphatases, there by modifying the DNA via alkylation or inhibit purine or pyrimidine synthesis. The enzyme inhibitors such as azathioprine, methotrexate and mycophenolate mofetil are non-peptide drugs that initiate the immunosuppressive activity by blocking the purine and pyrimidine synthesis. Monoclonal antibodies exhibiting high specificity towards their appropriate protein epitopes can inhibit target molecules which are used in immunotherapies.

The immunosuppressive agents currently available for therapy can be broadly categorized into three groups namely induction agents, maintenance therapeutics and agents in treatment for rejection. The drugs used in treatment for rejection group can be further divided into acute cellular rejection and acute humoral rejection. The immunosuppressive used as induction agents include polyclonal antibodies (anti-thymocyte globulin) and interlukin (IL)-2 receptor antagonists. In case of maintenance regimens, corticosteroids, anti- proliferative agents, calcineurin inhibitors, and mTOR inhibitors are used. For treating mild organ rejection corticosteroids and for moderate to severe condition of rejection cases anti-thymocyte globulins are used. Other side effects include hypertension, peptic ulcers, dyslipidemia, lipodystrophy, hyperglycemia, liver toxicity and kidney injury. The immunosuppressive drugs can interact with other drugs when taken simultaneously which result in poor metabolism and decreased action. The immunosuppressive agents whether actual or suspected can be evaluated based on their effects on lymphocyte subpopulations in tissues by applying immunohistochemistry.

Ongoing researches aim to develop therapeutic moiety which can treat autoimmunity without any side effect. Several peptides synthesized from ribosomes, due to their enhanced selectivity and decreased toxicity, are identified as potential therapeutic moiety. These bioactive peptides can target to the molecular action. The role of peptides as immunosuppressant is not only limited to disruption of antigen recognition alone, but rather it initiate the action through diverse mechanism such as inhibition of cell cycle programme, induction of apoptosis, and altering of signal transduction. The peptides or other compound derived from them represent an exciting new form of immunotherapy.

Researchers have found various signaling pathways and associated signaling molecules that identify target sites for new drug discovery for treating autoimmune disease, organ transplantation and allergic reactions caused by over reactive immune response. Ribosomally synthesized peptides are gaining importance in pharma sector for their selective action and decreased toxicity.  Among the peptides, circular peptides exhibit remarkable stability and are suitable for oral administration. Plant cyclotides are an attractive pharma tool which can effectively inhibit T lymphocyte proliferation. Peptides synthesized from non-ribosome have a variety of therapeutic activities such as immunosuppressive, anti tumor and anti bacterial activities. Their activity in pharmaceuticals are due to its structural diversity containing unique building blocks like heterocyclic elements, sugar moieties, fatty acids, D-amino acids and formulated residues.

The peptides coming under ribosomally synthesized peptides class are Collutellin A, Cyclosporine A, Antamides, Didemnin A/B, Ascomycin, Homophymines, Hymenistatin, Jasplakinolide, Sirolimus and Geodiamolides- however, they yet to enter the market. The non-ribosomally synthesized peptides include Cyclosporine A, Tracrolimus and Sirolimus, they initiate the action by interfering in cytokine signaling. Cyclic peptides obtained from fungus (Tolypocladium inflatum) are used widely in the treatment of autoimmune disease and are also used to prevent allograft rejection of transplanted organs. The class of peptides coming under ribosomally synthesized and post-translationally modified peptides are Cyclolinopeptide A/B, Iberiotoxin, Kalata B1, Magatoxin, Kaliotoxin, Charybdotoxin.  Biologically important peptides can be produced nonribosomally by utilizing multienzyme complexes like nonribosomal peptide synthetases (NRPS). The peptides prepared non-ribosomally not only contain the common 20 amino acid, but also hundreds of differing building blocks. The maturation of a product derived from nonribosomal peptide synthetases are initiated by tailoring enzymes. These enzymes can be further modified for preparing peptide backbone like C-and N- methylation, halogenations, oxidation and cross-linking properties, there by modifying the structural diversity of natural products and preserve the structural stability and rigidity from proteolitic digestion.

Development through chemoenzymatic for engineering nonribosomal peptides product were initiated for enhancing their bioactivities. Another approach in formulating nonribosomal peptides product is by combining chemical synthesis with cyclization mediated by nonribosomal thioesterase domain. Cyclic peptides are formed by linking one end of peptide and an amide body or by other stable bonds like ether, thioether, lactone, disulfide etc, have various biological activity. Some of the cyclic peptides found in nature are used in clinical practice (cyclosporine A with immunosuppressive activity).

Synthetic peptides are also studied for using as immunosuppressive, specifically synthetic peptides derived from ß1 domain of HLA-DR antigens containing RFDS and another peptide derived from immunoglobulin-like amino-terminal domain of CD4 containing RADS. Their inhibitory activities are similar to those exhibited by anti-CD4 and HLA-DR antibodies. The immunosuppressive region present in any retroviral envelop proteins like CKS-17 peptide corresponding to aa 533-549 of murine leukemia can be used to get synthetic peptides for inhibiting immune function in vitro and in vivo. Thalassospiramides A and B, two new cyclic peptides were isolated from marine alpha-proteobacterium thalassospira show immunosuppressive activity by interrupting the interleukin-5 production inhibition.

In a study with rat model of tolerogenic liver transplantation, the recipient serum was found to exhibit a strong immunosuppressive activity. The portion exhibiting the immunosuppressive factor was found to be transplantation-induced IgG antibody as histone H1. The in vivo studies have revealed that the polyclonal antibody raised against histone H1 suppressed the allogeneic mixed lymphocyte reaction (MLR). The studies further showed that the allograft survival was prolonged. To understand the mechanisms underlying the immunosuppressive activity a murine anti-histone H1 monoclonal antibodies (mAbs) termed 16G9- was raised for suppressing the MLR. The mAbs 16G9 have shown dose- dependent MLR activity. Further analyses with flow cytometer have also shown that 16G9 specifically react with part of murine splenocytes including T cells, B cells and CD11b+ monocytes/macrophages. The findings indicate the possibility that 16G9 may suppress MLR via cross-reaction with target antigens on leukocytes. The peptidic inhibitors of heme oxygenase were originally developed from the immunomodulatory peptide 2702.75-84, which corresponds to the amino acid residues 75 to 84 of the a1-helix of HLA-B2702 (2702.75-84) and found to have immunosuppressive activity both in vitro and in vivo.