Immunosuppressants Flashcards
What is the 1st line of defense against invading pathogens?
Innate Immune System
What are the 3 normal functions of the immune system (very broad)
1) Neutralize toxins
2) Destroy transformed cells
3) Eliminate pathogens
Agents that increase or decrease the immune response. Selectively alter the balance of the components of the Immune System.
Immunopharmacology
What are the mechanical components of the Innate Immune System?
Skin and Mucus (contains enzymes to break down pathogens)
What are the biochemical components of the Innate Immune System?
Antimicrobial peptides & proteins
Complement
Enzymes
Interferons
Free Radicals
What are the cellular components of the Innate Immune System?
Neutrophils
Monocytes
Macrophages
Natural Killer (NK) and Natural Killer T-Cells (NKTs)
What is the immediate innate response?
Inflammation
When the skin or mucus is breached, an immediate _____ response is provoked that leads to the destruction of the _____.
Inflammatory; pathogen.
True/False: The Innate Immune System response is antigen specific.
False
Mobilized by cues from the Innate Immune System when it is incapable of coping with the infection.
-Produces antibodies
-Activates T-Lymphocytes
Adaptive Immune System
The _____ Immune System responds to a variety of antigens in a specific manner.
Adaptive
The Adaptive Immune System can discriminate between ____ antigens and _____ antigens.
Foreign; Self
Activation of T-lymphocytes is regulated by what?
A negative feedback loop
The Adaptive Immune System responds to a _____ _____ antigen.
Previously encountered
Molecules that stimulate an immune response either by antibody production or lymphocyte stimulation
Antigens
Specific proteins called Immunoglobulins (Ig) which recognize and bind to specific antigens.
-5 Classes
Antibodies (IgG, IgA, IgM, IgD, IgE)
Activated by binding with foreign antigens and secrete mediators to regulate the immune response.
-4 sub classifications
T Cells
When activated, differentiate into plasma cells that synthesize antibodies
-Controlled by the T Cells
-4 types
B Cells
Do not require specific antigen stimulation to work. Potent killers of virally infected cells.
Natural Killer Cells
A signal that attracts other key players in the immune system to the site of inflammation.
Chemotaxis
The process of coating bacteria to facilitate their ingestion.
Opsonization
Proteins that further the immune system response by attracting phagocytes to the inflammatory site (C3a & C5a), forming a Membrane Attack Complex (MAC) that lyses bacteria (C5b - C9), or by coating bacteria (opsonization) and facilitating their digestion/ingestion by phagocytes (C3b)
Complement
The _____-_____ part of the immune response involves the ingestion/digestion of antigen by antigen presenting cells (Macrophages)
Cell-Mediated
The macrophage (APC) binds with a T Lymphocyte. If it binds with a TH1, it will go down the _____pathway. If it binds with a TH2, it will go down the ____ pathway.
TH 1 = Cell-Mediated Pathway
TH 2 = Humoral Pathway
Leads to the production of:
-IFN Gamma & TNF: Additional activated macrophages
-IFN Gamma: Activated NK cells
-Activated Cytotoxic T Cells
TH 1 (Cell Mediated Pathway)
Leads to proliferation & differentiation.
-Proliferation: Memory Cells
-Differentiation: Plasma Cells -> Antibody
TH 2 (Humoral Pathway)
What are the negative feedback loops that offer downregulation of the Adaptive Immune System? (regulated both TH2 and TH1)
IL 10 and IFN Gamma
Which is the only type of hypersensitivity that is not Antibody Mediated?
Type 4 (Delayed - Cell Mediated)
What are the two phases of Hypersensitivity?
1) Sensitization Phase (Occurs on the initial contact with an antigen)
2) Effector Phase (Occurs upon subsequent encounter with an antigen; involves immunologic memory)
-IgE Mediated
-Exposure to insect venoms, foods, drugs, or pollens
-Onset is within minutes
-Related to Histamine, Leukotrienes, and Eosinophils
-Reactions: Anaphylaxis, hayfever, asthma, urticaria, hives, angioedema
Type 1 Hypersensitivity
Type 1 Hypersensitivity is _____
“Immediate”
-IgM or IgG
-ABO incompatibility, hemolytic dz of the newborn, or known drug allergy; HITT
-Onset is minutes to hours
-Involves Complement Dependent Lysis or Antibody Dependent Cellular Cytotoxicity
-Rxn: Red Cell Lysis, Hemolytic anemia, Granulocytopenia, Thrombocytopenia
-Tx: Anti-inflammatories and immunosuppressants
Type 2 Hypersensitivity
Type 2 Hypersensitivity is ______.
“Cytotoxic”
-IgG & elevated levels of antibody-antigen complexes
-Causes: Particular antigen, drugs, vaccines, antivenoms
-Onset is 3-4 days after exposure
-Involves Complement mediated vasculitis
-Rxn: Skin rashes, glomerulonephritis, arthritis, or vasculitis
Type 3 Hypersensitivity
Type 3 Hypersensitivity is ______
“Serum Sickness”
Involves circulating antibody-antigen complexes that are deposited in the microvasculature. Neutrophils and plts respond to site and cause tissue damage.
Type 3 Hypersensitivity
-Antigen Specific TH1 Cells
-Causes: A particular antigen (examples: TB, Leishmaniasis, Poison Ivy)
-Onset is 2-3 days after exposure
-Involves DTH T-Cell Response, local inflammatory response causes tissue damage
-Rxns: Allergic contact dermatitis
Type 4 Hypersensitivity
Type 4 Hypersensitivity is _____.
“Delayed”
Occurs when the body mounts an immune response against itself.
-Body fails to distinguish endogenous self cells & tissues from exogenous non-self antigens
-Loss of tolerance to self
-Involves the activation of T&B Lymphocytes (generates a cell-mediated or humoral mediated response against self antigens)
Autoimmunity
Occurs when IgM antibodies react with IgG and form immune complexes that activate the complement cascade. The Immune complexes seat themselves in joints, causing damage.
-Chronic inflammation of the joints and kidneys (leads to long-term kidney damage)
-Issues with airway due to joint immobility!
Rheumatoid Arthritis
Occurs when antibodies form against DNA, Histones, RBCs, Platelets, Etc.
-Overall body inflammation, including joints, skin, kidneys, brain, heart/lungs
-Characterized by periods of remission
-S/Sx: Butterfly rash (Dermatitis is primary to the dz process)
-Tx: Symptom and trigger control
Systemic Lupus Erythematosus
The destruction of the myelin of nerve cells.
-Can damage sensory or motor nerves
-Cognitive issues, limb weakness, muscle spasms
-NO spinal anesthesia!! (don’t promote MSK weakness)
Multiple Sclerosis
Destruction of the Islet Beta Cells of the Pancreas
Type 1 Diabetes (Insulin-Dependent)
Arise from inadequate or dysfunctional immune system.
-Causes: Congenital, bacterial/viral, drugs
-Individuals are frequently effected by opportunistic infections
-Ex: HIV/AIDS (Depletion of the CD4 T Helper Cells; inc frequency of opportunistic infections)
Immunodeficiency Diseases
Failure of the B-Lymphocytes to mature into antibody producing plasma cells
-Effects males; females are carriers
-Susceptible to recurrent bacterial infections (but are able to fight viral/fungal infections because cell-mediated immunity is still intact)
X-Linked Agammaglobulinemia
Failure of the thymus to develop, resulting in a lack of a T-Cell response.
-Humoral immunity remains intact
-Defect of Chromosome #22
-S/Sx: Cyanosis/CHD; Breathing issues; spasms of hand, mouth, arms, & throat; developmental delay; airway: Micrognathic underdeveloped chin (!!); Low set ears; cleft lip/palate
DiGeorge Syndrome
Loss of all Adaptive Immunity due to Adenosine Deaminase Deficiency (ADA).
-Death of T&B Cells
-Innate immunity works fine, but it is insufficient
Severe Combined Immunodeficiency Syndrome (SCID)
Drugs that minimize the occurrence and/or impact of abnormal immune responses.
Immunosuppressive Agents
What are the 8 Classes of Immunosuppressive agents?
1) Glucocorticoids
2) Calcineurin Inhibitors
3) Mammalian Target of Rapamycin (mTOR) Inhibitors
4) Mycophenolate Mofetil
5) Immunomodulatory Derivatives of Thalidomide
6) Cytotoxic Agents
7) Immunosuppressive Antibodies
8) Monoclonal Antibodies
Continuous administration of this class of drug increases the fractional catabolic rate (breakdown) of IgG.
-Lowers the effective concentration of antibodies
Uses:
-Used as 1st line immunosuppressive therapy for solid organ tumors and stem cell transplants (!)
-Modulates allergic rxns
-Tx of diseases (asthma)
-Premedication (blood products or Chemo)
Glucocorticoids
What are the 2 Calcineurin Inhibitors?
Cyclosporine & Tacrolimus (ProGraf)
What is the same for both Calcineurin Inhibitors (both Cyclosporine & Tacrolimus (ProGraf))?
1) Both Block T-Cell Activation
2) Both are used in organ transplant and to treat graft vs host dz
3) Both are metabolized by the P450 system
4) Toxicities for both include Nephrotoxic, HTN, Hyperglycemia, and Hyper K+
A peptide ABX that blocks T-Cell Activation
-Used for organ transplant or graft vs host
-IV or PO
-Toxicities: Nephrotoxic, seizures, HTN, Hyperglycemia, Liver Dysfunction, Hyper K+
-Inc incidence of Lymphoma and other cancers
-Combined with glucocorticoids
Cyclosporine
A macrolide ABX that blocks T-Cell Activation.
-10-100 times more potent than the other drug in its class
-Can be given topically for atopic dermatitis or psoriasis (in addition to IV/PO for organ transplant/GVHD)
-Toxicities: Nephrotoxic, Neurotoxic, Hyperglycemia, HTN, HyperK+
-Often combined with Methotrexate or MMF
Tacrolimus (ProGraf)
More potent than Cyclosporine
What are the 2 drugs that are mTOR Inhibitors?
Sirolimus (Rapamycin) and Everolimus (Zortess)
Macrolide ABXs that are mTOR antagonists (inhibits T-Cell Proliferation).
-Used in organ transplant and GVHD
-Cause profound bone marrow suppression, thrombocytopenia, hepatotoxicity, inc Cholesterol
-Used in drug-eluting stents to reduce restenosis in pts with severe CAD
-Can be used alone or in combo with Corticosteroids, Cyclosporine, Tacrolimus, or MMF.
-High risk for antibodies to blood and need irradiated or leukoreduced RBCs
Sirolimus (Everolimus is basically the same thing)
What is the only difference between Sirolimus and Everolimus?
Everolimus has better bioavailabiliy than Sirolimus
A semisynthetic derivative of mycophenolic acid that inhibits purines (remember: We need purines to build DNA).
-1st line tx for preventing chronic allograft vasculopathy in cardiac transplants
-Also used in tx of GVHD, lupus nephritis, RA, IBD, & Derm Disorders
-Given post-op for transplant patients
-Toxicities: Myelosuppression and neutropenia (kills off WBCs, particularly neutrophils)
-Neutropenic precautions
Mycophenolate Mofetil (MMF) (Cell Cept)
A sedative from the 1960s originally designed for the suppression of morning sickness.
-Withdrawn due to severe teratogenicity (stunted growth of arms & legs)
Thalidomide
What are the 2 drugs in the IMiDs Class (Immunomodulatory)?
Thalidomide and Lenalidomide
-Inhibits angiogenesis and TNF-Alpha
-Reduces phagocytosis by neutrophils
-Increases production of IL10 (negative feedback)
-Enhances T-Cell interactions
Thalidomide and Lenalidomide
Used to treat multiple myeloma, leprosy, and skin issues of lupus
-Toxicities: Teratogenic, high risk of DVT (pts were placed on anticoagulants)
Thalidomide
Uses: Myelodysplastic Syndrome and Multiple Myeloma
-Much less teratogenic and less risk of DVT
-Toxicities: peripheral neuropathy, constipation, rash, fatigue
Lenalidomide
Impairment of delayed hypersensitivity and cellular immunity
-Humoral immunity stays intact
-Used in organ transplant/bone marrow transplant to induce immunosuppresion
-Can be used to treat initial rejection or treatment of steroid resistance rejection
-Toxicities: Local pain and erythema at injection site; Serum Sickness Rxn (type 3); Anaphylaxis (Type 1)
Antilymphocyte (ALG) and Antithymocyte (ATG) Antibodies
A 15% solution of human IgG containing antibodies against the Rho(D) antigen of RBCs.
-Based on the premise that the primary antibody response to a foreign antigen can be blocked if specific antibodies to that antigen are administered passively at the time of exposure to the antigen.
-Prevents hemolytic dz of the newborn
RH(o)D Immune GLobulin (Rhogam)
Given prophylactically for acute organ rejection in renal transplant patients.
Basiliximab (monoclonal antibodies)
Occurs with an RH- mom has an RH+ baby. RBCs burst, babies are born without O2 carrying capacity
-Erythroblastosis fetalis in the 3rd trimester of subsequent pregnancies as a result of the transfer of maternal antibodies against RH+ cells to the fetus
-Given Rhogam 28 wks for any RH- mom and also 24-72 hours after birth of the RH+ infant.
-Rhogam removes the blood products of the fetus that are in mom’s circulation before she can develop antibodies
Hemolytic Disease of the Newborn
Organ rejection that occurs within hours of transplant.
-Due to preformed antibodies against the donor organ
-Rapid necrosis & failure of the transplanted organ
-Cannot be stopped
Hyperacute Organ Rejection
Organ rejection that is mediated by Antibodies and T Cells
-Occurs within 2-3 days
-Cannot be stopped
Accelerated Organ Rejection
Organ rejection that is mediated by cellular immunity
-Occurs within days to months
-Reversal with general immunosuppressants
Acute Organ Rejection
Organ rejection that is r/t the thickening and fibrosis of the vasculature of the transplanted organ
-Mediated by cellular and humoral immunity
-Occurs within months to years
-Reversal with general immunosuppressants
Chronic Organ Rejection
-HLA Matched Donor
-Patient develops a new immune system generated by the donor stem cells
-Rejection of stem cells is uncommon
-GVHD occurs in the majority of patients
-Treats autoimmune disorders with varied success (such as ITP, Hashimotos, SLE, RA, Scleroderma, Etc).
Bone Marrow Transplant
-Occurs within the first 100 days
-Skin rash, severe diarrhea, hepatotoxicity
-Tx: High dose corticosteroids plus + one of the following: MMF, Sirolimus, Tacrolimus, or Daclizumab
Can progress to pancytopenia - high fatality rate
Acute Graft (transplant) vs Host (person receiving the transplant) Disease
Occurs after the first 100 days
-Can resolve within 1-2 years
Chronic Graft vs Host Disease
