IMMUNOLOGY
Introduction:
The immunity system has evolved to protect the host from invading pathogens and to eliminate the disease. When functioning at its best, the immune system is exquisitely responsive to invading pathogens while retaining the capacity to recognise self-tissues and antigens to which it is tolerant. Protection from infection and disease is provided by the collaborative efforts of the innate and adaptive immune system.
The innate immune system is the first line of defence against invading pathogens like bacteria, viruses, fungi and parasites. It consists of mechanical, biochemical and cellular components. Mechanical components of this system comprise epidermis and mucus. Biochemical components include antimicrobial peptides and proteins, complement, enzymes, interferons, acidic pH, and free radicals. Cellular components include neutrophils, monocytes, macrophages, natural killer cells, and natural killer T cells. Innate immune response exists before infection but it is not enhanced by repeated infection and is not antigen-specific.
The adaptive immune system is mobilized by cues from the innate response when the innate processes are incapable of coping with an infection. This system has several characteristics that contribute to its success in eliminating pathogens. These include the ability to
1. Respond to a variety of antigens, each in a specific manner.
2. Discriminate between foreign antigens and self-antigens of the host, and
3. Counter the previously experienced antigen in a learned way by initiating a vigorous memory response.
This adaptive response culminates in the production of antibodies, which are the effectors of humoral immunity; and the activation of T lymphocytes, which are the effectors of cell-mediated immunity.
THERAPEUTIC INDICATIONS:
Abnormal immune responses:
Normally functioning immune response can successfully neutralize toxins, inactive viruses, destroy transformed cells and eliminate pathogens, but an inappropriate response can lead to extensive tissue damage i.e hypersensitivity or reactivity against self-antigens i.e. autoimmunity and impaired reactivity to appropriate agents resulting in immunodeficiency.
Hypersensitivity:
It can be classified as antibody-mediated or cell-mediated. There are three types of hypersensitivity such as antibody-mediated type I-III, while the fourth is cell-mediated type IV. Hypersensitivity occurs in two phases
1. The sensitization phase that occurs upon initial encounter with an antigen.
2. The effector phase that involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen.
Autoimmunity:
Autoimmune disease arises when the body mounts an immune response against itself due to failure to distinguish self-tissues and cells from foreign antigens or loss of tolerance to self. This process derives from the activation of self-reactive T and B lymphocytes
These diseases are highly complex due to environmental conditions, infectious entities, MHC genetics, and dysfunctional immune regulation. Examples of such diseases are rheumatoid arthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, and insulin-dependent diabetes mellitus.
Immunodeficiency diseases:
Immunodeficiency diseases are the results of the inadequate function in the immune system; the consequences include increased susceptibility to infections and prolonged duration and severity of the disease. These diseases are either congenital or arise from extrinsic factors such as bacterial or viral infections or drug treatment.
Affected individuals are generally frequently succumb to infections caused by opportunistic organisms of low pathogenicity for the Immuno-competent host. Examples are X linked agammaglobulinemia, DiGeorege’s syndrome, and severe combined immunodeficiency disease due to adenosine deaminase deficiency.
DRUG INDICATIONS:
Glucocorticoids:
These were the first hormonal agents recognized as having lymphocytic properties. Glucocorticoid reduces the size and lymphoid content of the lymph nodes and spleen, although it has no toxic effect on proliferating myeloid stem cells in the bone marrow.
It has beneficial effects on diseases such as idiopathic thrombocytopenic purpura and rheumatoid arthritis.They are first-line immunosuppressive therapy for both solid organ and hematopoietic stem cell transplant recipients, with variable results.
Cyclosporine:
It is an immunosuppressive agent with efficacy in human organ transplantation, in the treatment of graft-versus-host disease after hematopoietic stem cell transplantation. It is also used in the treatment of selected autoimmune disorders.
Cyclosporine is administered intravenously or orally due its low absorption about 20–50% only. The absorbed drug is primarily metabolised by the P450 3A enzyme system in the liver with resultant multiple drug interaction.
Tacrolimus:
It is an immunosuppressant macrolide antibiotic, not chemically related to cyclosporine, but their mechanisms of action are similar. Tacrolimus can be administered orally or intravenously. The half-life of its intravenous form is around 9–12 hours. The dosage is determined by blood level at a steady state.
Mycophenolate mofetil:
It inhibits T and B lymphocyte responses, including mitogen and mixed lymphocyte responses when administered in vitro. Mycophenolate mofetil is obtained in oral and intravenous forms. But the oral form is abruptly metabolized to mycophenolic acid.
It is used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who don’t tolerate those drugs.
Thalidomide:
Thalidomide is an oral sedative drug. It inhibits angiogenesis and has inflammatory and immunomodulatory effects. It inhibits tumour necrosis factor-alpha, reduces phagocytosis by neutrophils, increases the production of IL-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T-cells.
Thalidomide is currently used in the treatment of multiple myeloma at initial diagnosis and for the relapsed-refractory disease. Patients generally show signs of response rates within 2–3 months of starting the drug, with response rates of 20–70%.
Other drugs:
Drugs used for the treatment of cancer immunotherapy are abarelix, aclarubicin (to treat leukaemia), afatinib, blinatumomab, brigatinib, copanlisib, dimethylglycine, durvalumab, enasidenib, idelalisib, lenograstim, etc.
Drugs used to treat melanoma are ipilimumab, nivolumab, pembrolizumab, etc.
Other drugs that come under immunology are astepro, azaSite, barracuda, ascend, cefazolin, cedax, cayston, confide, Combivir, Cleocin, cosentyx, dificit, daptacel, doribax, and many more.
Cytotoxic agents:
Azathioprine is a prodrug of mercaptopurine functions as an antimetabolite.
Cyclophosphamide is also an immunosuppressive drug available.
Leflunomide is a prodrug of an inhibitor of pyridine synthesis.
Teriflunomide, both inhibit the mitochondrial enzyme dihydroorotate dehydrogenase.
Hydroxychloroquine is an antimalarial agent with immunosuppressant properties.
Other agents are methotrexate, vincristine and cytarabine.
