Treatments to Modulate the Host Immune System Flashcards
exogenous immune suppression two pathways
- Using chemicals or agents that
are broad or non-specific in that they can also suppress the activity of other cell types in the
body. - specific in which the target is a specific immune cell or mediator. We will first review the chemicals and agents that can be used to non- specifically suppress the immune system.
Non-specific Immunosuppressants:
corticosteroids, cytotoxic drugs, radiation tx
what are corticosteroids
This group of drugs are the most commonly and widely used
immunosuppressive and anti-inflammatory drugs in human and veterinary medicine.
Interestingly, their level of efficacy differs by species. For example, humans and rodents are
more corticosteroid sensitive than the domestic veterinary species. The important point is that the
type and dose of corticosteroid use will be dictated by the species receiving the drug.
Corticosteroids are classified as either glucocorticoids (i.e. anti-inflammatory) or
mineralocorticoids (i.e. salt retainers). As glucocorticoids, they suppress inflammation and
immunity, while also modulating the breakdown of carbohydrates, fats and proteins. As
mineralocorticoids, they can regulate the salt and water balance in the body. One last point,
corticosteroids can have different effects on different cells in the body
mode of action of corticosteroids
The drug, due to it lipophilic properties, can easily gain entry in to the host cells
and bind to cytoplasmic corticosteroid receptors. These complexes then enter the nucleus where
alters protein synthesis. Depending on the cell type, it can affect the protein that is synthesized
and thus, the function of the cell (i.e. metabolic function of cells, cell membrane permeability. In
immune cells, it can increase the production of the protein IκBα which is typically bound to the
transcription factor NF-κB in the cytoplasm of resting immune cells. Normally when immune
cells become activated, IκBα is cleaved and digested by proteasomes in the cytoplasm and NF-κB is trafficked into the nucleus where initiates protein synthesis of potent proinflammatory
cytokines. Corticosteroids block this protein synthesis by preventing the trafficking of NF-κB
into the nucleus by providing more IκBα to rebind to the NF-κB. Corticosteroids can also inhibit
phospholipase A, which is important in arachidonic acid synthesis, an important molecule
involved in the formation of potent inflammatory mediators
4 areas associated with general effects of corticosteroids
Corticosteroids can alter the metabolism of carbohydrates, fat and proteins. As described
above, they alter the activities of inflammatory mediators. They can modulate leukocyte
production and circulation (i.e. decreased chemotaxis and phagocytosis). Lastly, they can alter
the effector function of lymphocytes (i.e. decreased proliferation, IL-2 production T cell
function)
risks associated with corticosteroids
Long term administration of corticosteroids can
suppress the adrenal-pituitary axis leading to a disease known as Cushing’s syndrome
the common synthetic corticosteroids administered in humans
prednisone, prednisolone,
methylprednisolone and dexamethasone
the common synthetic corticosteroids administered in companion animals
prednisolone and
methylprednisolone
the common synthetic corticosteroids administered in large animals
betamethasone and dexamethasone
what are targeted treatments of corticosteroids
allergies, arthritis, asthma, skin rashes and colitis
list of cytotoxic drugs
alkylating drugs, folic acid antagonists, DNA synthesis inhibitors
alkylating drugs
cytotoxic drugs that broadly work, mode of action, by
adding an alkylating agent to a guanine base on DNA in actively dividing cells. This
results in cross-linking DNA helices resulting in DNA strand breaks, preventing cell
division leading to the death of the cell. These were one of the first class of drugs to
treat cancer (i.e. antineoplastic or anti-cancer drug) as early as the 1940’s and are
classified as a chemotherapeutic drug. There are 5 types of alkylating agents: nitrogen
mustards, nitrosoureas, alkyl sulfonates, triazines and ethylenimines.
Cyclophosphamide (cyclophosphane, cytoxan), a nitrogen mustard, is one of the most
well-known and commonly used of the alkylating agents and requires metabolism in the
liver in order to become active. It has tremendous suppressive effects on T cell and B cell
function as well as being myelosuppressive
Cyclophosphamide
in addition to being immunosuppressive, has been used to treat
lymphoma, multiple myeloma, breast cancer, neuroblastoma, ovarian cancer, small cell
lung cancer and sarcoma
Folic Acid Antagonists
class of drugs that block cells from using folic acid to
synthesize DNA constructs making it also an effective anti-neoplastic drug.
Methotrexate is classic folic acid antagonist that binds to dihydrofolate reductase
preventing the synthesis of tetrahydrofolate, which blocks the synthesis of thymidine
and purine nucleotides
Methotrexate
can suppress antibody formation and as a result also has good efficacy
against rheumatoid arthritis and severe psoriasis
DNA Synthesis Inhibitors
similar to folic acid inhibitors, DNA synthesis inhibitors block
DNA synthesis. Azathioprine (Imuran) functions as a nucleoside analog to block DNA
synthesis. It is converted in the liver to 6-mercaptopurine via thiopurine
methyltransferase resulting in the inhibition of both RNA and DNA synthesis
Azathioprine
can suppress both primary and secondary antibody responses as well as T
cell-mediated response and macrophage production. It is also myelosuppressive. It is
used to treat cancer, dermatomyositis, inflammatory bowel disease, rheumatoid arthritis,
lupus (SLE), vasculitis and commonly partnered with corticosteroids.
Radiation treatment
Radiation exists as two different forms, non-ionizing and ionizing.
In general, the non-ionizing form of radiation tends to be safe. It is the ionizing
form that tends to be the more detrimental to the cells and/or host. Ionizing radiation emits as
high energy, that upon entry into the cell, can directly damage DNA as well as ionizes water
molecules forming free radicals in the cells. Both forms of cell damage can result in cell death.
Radiation therapy can originate from an external source (i.e. gamma radiation accelerator) or
placed inside the body known as brachytherapy using radiative beads, one treatment for prostate
cancer
In the past, it has been used to suppress immunity, in particular T cells, in graft transplants for
research animals, it is not a practical tool in human or veterinary medicine
Specific or Selective Immunosuppressants
Calcineurin Inhibitors (CNI) (cyclosporine), mTOR (Mechanistic Target of Rapamycin) Inhibitors (rapamycin), Inosine Monophosphate Dehydrogenase Inhibitors (Mycophenolate mofetil), Leflunomide (Arava), Intravenous Immunoglobulin Therapy (IVIG)
Calcineurin Inhibitors (CNI)
family of drugs (cyclosporine, pimecrolimus, and
tacrolimus) with potent selective immunosuppressive properties. Broadly speaking, their mode of
action is to block T cell proliferation via the inhibition of the key signaling phosphatase
calcineurin. Cyclosporine binds to the intracellular protein cyclophilin. Tacrolimus binds to FK-
binding protein and pimeocrolimus binds to macrophilin-12. When these complexes are formed
within the cell, calcineurin is inhibited and T cell activation is blocked
Cyclosporine
most well-known and utilized polypeptide product of
the soil fungus, Tolypocladium inflatum, which naturally yields several forms of the peptide.
Cyclosporin A is a circular 11 amino acid with 2 protein binding sites. Upon entry into T cells, it
binds to cyclophilin at one site and calcineurin, a serine threonine phosphatase, with the other
site. This effectively shutdowns down signal transduction inhibiting IL-2 and IFNγ resulting in
the downregulation of Th1 response. Along with corticosteroids, this drug combination is quite
effective in controlling against immune-mediated graft rejections.
mTOR (Mechanistic Target of Rapamycin) Inhibitors
Mechanistic target of rapamycin
(mTOR) is a key nutrient-sensitive regulator of cell growth in animals with a major role in cell
physiology, metabolism, aging and when upregulated, can lead to disease such as cancer. It
functions as the catalytic subunit for two protein complexes, mTORC1 and mTORC2.
Downregulation or inhibition of mTORC1 is associated with increased lifespan in animal models
(i.e. rodents)
rapamycin
an inhibitor of mTOR, is a natural anti-fungal antibiotic of soil bacteria of
the Eastern Island. quite effective in regulating T cell activation, inhibiting T cell and B cell
proliferation and can promote tolerance. It is often paired with a calcineurin inhibitor to prevent
graft rejection. Recently, this drug and its synthetic analogs or rapalogs has received a lot of
attention as a possible treatment to extend the quality and length of life. Based on its mode of
action, it does make some sense although more studies are needed in this area
Inosine Monophosphate Dehydrogenase Inhibitors:
Inosine Monophosphate Dehydrogenase
is responsible for the rate limiting step in the de novo synthesis of guanine nucleotides. Guanine
nucleotide synthesis is critical for normal cell function and growth as well as the immune
response
