Quiz 2 Exam 4 Flashcards
Hypersensitivity and allergies
Hypersensitivity is an _____________ of the immune system
Over-reaction
Hypersensitivity reactions are immune reactions that are __________ against an _________.
Exaggerated
Antigen
In the classification of hypersensitivity reactions by Coombs and Gell, what is the mechanism behind type I/ immediate type hypersensitivity reactions?
Type 1 hypersensitivity reactions are IgE mediated with mast cells and basophils. This response can be rapid or delayed
In the classification of hypersensitivity reactions by Coombs and Gell, what is the mechanism behind type II/ antibody-mediated cytotoxic hypersensitivity reactions?
Type II hypersensitivity reactions are IgG and IgM mediated. This response can be from hours to days.
In the classification of hypersensitivity reactions by Coombs and Gell, what is the mechanism behind type III/ immune complex mediated hypersensitivity reactions?
Type III hypersensitivity reactions are mediated by antigens and antibodies as well as IgG and IgM. This response can take hours to weeks.
In the classification of hypersensitivity reactions by Coombs and Gell, what is the mechanism behind type IV/ T cell-mediated hypersensitivity reactions?
Type IV hypersensitivity reactions are mediated by T lymphocytes and cytokines. This reaction can last days to weeks.
The initial exposure in type I hypersensitivity reactions is due recognition of T cells and presentation of MHC molecules which stimulates plasma cells to produce __________. That will binds to basophils and mast cells and stimulate the release of granules with inflammatory mediators.
IgE
When IgE binds to mast cells and basophils in the type I hypersensitivity reaction, what mediators are released in response?
Granules and inflammatory mediators
What are some of the different mediators released by mast cells?
They release preformed mediators like histamine, heparin, proteases, and TNF. THey release lipid mediators like prostaglandins and leukotrienes, and they release cytokines and chemokines.
What are the main actions of the different mediators released by mast cells in a type I hypersensitivity reaction?
Vasodilation, increased vascular permeability, smooth muscle spasms, and leukocyte extravasation.
Cytokine releases increases vascular permeability which shifts fluid from intravascular to extravascular space. What is the result of intravascular depletion?
This results in decreased perfusion of tissues and organs. It also decreased blood pressure and reflexively increases heart rate.
Cytokine releases increases vascular permeability which shifts fluid from intravascular to extravascular space. What is the result of extravascular accumulation?
Edema
Allergy is a hypersensitivity reaction in which ________________ mediated hypersensitivity is prominent.
IgE
Thinking about drug allergies, what is the main thing to determine in patients?
Identify patients at risk for hypersensitivity reactions.
What is the physiology surrounding anaphylaxis?
Mast cells suddenly release a large amount of histamines and leukotrienes which leads to intense bronchospasms, laryngeal edema, cyanosis, hypotension, and shock.
In a very basic sense, anaphylaxis is a very severe __________ hypersensitivity reaction.
Type I
What is the clinical criteria for an anaphylaxis diagnosis?
- Acute onset of the illness with involvement of skin, mucosal tissue, or both
- ONE OF THE FOLLOWING
A. Respiratory compromise
B. Reduced BP or symptoms of end-organ dysfunction
C. Severe GI symptoms
What are the 3 goals in the management of type I hypersensitivity reactions?
- Inhibit mast cell degranulation
- Antagonize mast cell mediators
- Reduce inflammation
What is the main drug given in anaphylaxis?
Epinephrine
What are the effects of epinephrine?
VAscular smooth muscle cell contraction, increases cardiac output, inhibits bronchial smooth muscle cell contraction
How is anaphylaxis managed long-term?
Identify the triggers and create a written action plan. Educate the patient and makes sure they have epi pens. All about preventing the recurrence to prevent death.
What is the pathophysiology behind a type II hypersensitivity reaction?
Type II hypersensitivity reactions are antibody-mediated cytotoxic reactions. It is when IgG and IgM antibodies produced by immune responses bind to antigens on the individuals own cell surface. When these large immune complexes are formed, they can initiate the complement cascade.
Cellular destruction in type II hypersensitivity reactions occur via what 3 mechanisms?
Phagocytosis
Complement-dependent cytotoxicity (CDC)
Antibody-dependent cellular toxicity (ADCC)
What is the pathophysiology behind type III immune complex mediated hypersensitivity reactions?
There is an accumulation of antigen-antibody complexes (immune complexes) that are NOT cleared by innate immune cells. The immune complexes lead to complement activation and inflammatory responses mediated by neutrophils.
What is the pathophysiology behind type IV cell-mediated hypersensitivity?
This is triggered by autoimmune and exaggerated or persistent responses to environmental antigens.
T or F: Not all drug hypersensitivity reactions
can be classified with the system described by
Coombs and Gell.
True
T or F: All infusion-related reactions are allergic reactions.
False. They are often hypersensitivity related reactions but not always a true allergy.
What is an infusion-related reaction (IRR)?
Adverse reactions to an infusion of pharmacological or biological substances that can occur at anytime that patient is receiving it.
What is cytokine release syndrome?
A condition that may occur after treatment with some immunotherapies that stimulate an immune response via the release of cytokines. This results due to T cell activation.
What are the symptoms of cytokine release syndrome?
Fever, nausea, headache, decrease in BP, increased HR, and shortness of breath
What are immunotherapy-related toxicities (now called immune checkpoint inhibitor-related toxicities)?
This is the infiltration of normal tissue by activated T cells responsbile for autoimmunity due to inhibition of inhibitory receptors on T cells. Toxicities are related to autoimmunity and can happen in virtually an organ.
What are immune checkpoint inhibitor drugs?
In cancer, the inhibitory receptors on T cells can be upregulated. These drugs block their inhibitory receptors ramping up the immune system.
What mediates the immediate type I hypersensitivity reaction?
IgE
T or F: Cytokine release syndrome is an example of a type II hypersensitivity.
False
T or F: The diagnosis for anaphylaxis is clinical.
True
What are the strategies for the management of a hypersensitivity reaction?
Collect, Assess, Develop a plan for acute and delayed reactions and pick what drug therapy to use. Implement plan and communicate plan. Evaluate the impact of the plan and modify as needed.
Monoclonal antibodies are proteins with inherent ________________.
Immunogenicity.
Human MA are more immunogenic compared to chimeric then to mouse.
Monoclonal antibody hypersensitivity reactions may be due to ____________ __________.
Cytokine release (cytokine release syndrome)
How can symptoms of infusion-related reactions be prevented?
- Premedication of antihistamines, corticosteroids, and acetaminophen
- Titration of infusion and splitting of the infusion over several days
If someone begins have a reaction to an infused drug, what is the first thing to do?
Stop the drug
If someone has an immediate infusion toxicity, what are the steps to manage it?
- Stop the drug
- Assess clinical status of patient
- Supportive care
- Give meds based on clinical symptoms
Platinum agents like cisplatin, carboplatin, and oxaliplatin have a higher than usual risk of hypersensitivity reactions. By what infusion cycle are most reactions to these drug seen?
5 cycles
What is drug desensitization?
This is induction of a temporary state of drug tolerance in a patient with hypersensitivity to the drug. In order to maintain the temporary state of tolerance, the patient must continue to take the medication regularly. This is only acceptable if there are no known alternative drugs.
What are the medications given prior for desensitization?
Antihistamines and corticosteroids
T or F: Those who have penicillin allergies are likely not allergic to antibiotics with similar chemical properties to penicillin.
False. They will likely have an allergic reaction to those drugs as well.
What are some strategies to decrease cytokine release syndrome with agents known to cause this adverse reaction?
Premedication
Step-up dosing
Monitor in the hospital
Autoimmunity is a hypersensitivity response where the antigen is a _______ antigen.
self
What is immunological tolerance?
This is an unresponsiveness of the adaptive immune system to self antigens. Also known as self tolerance. It is the ability of the immune system to prevent itself from targeting self.
What are the 3 mechanisms of immune tolerance?
- Non-reaction of self-reactive lymphocytes induced by self-antigens
- Inactivation of self-reactive lymphocytes
- Death of self-reactive lymphocytes
_________________ play an important role in
maintaining immune tolerance.
Regulatory T cells
What is the role of regulatory T cells?
T reg cells may suppress immune response of other cells. They are like a self-check built into the immune system to prevent excessive reactions. They should prevent autoimmunity
T or F: T regulatory cells prevent autoimmunity.
True
Autoimmune diseases are a diverse
group of conditions characterized by
aberrant ______ and ______ reactivity to normal constitutions of the host.
B cell
T cell
Autoinflammatory diseases are a dysregulation of the _________ immune system that occurs in predisposed hosts, sometimes with secondary activation of adaptive immunity, resulting in inappropriate inflammation. There are no self-reactive ____________ here.
Innate
Lymphocytes
T or F: Inflammation against self tissues is always dependent on abnormal T and B cell responses.
False.
T or F: Not many autoimmune diseases are heterogenous and multifactorial.
False.
How do autoimmune diseases develop?
There are always a small number of self-reactive T and B cells that can leak out into the periphery. They will remain harmless unless there is a genetic predisposition or environmental trigger to break tolerance.
T or F: The inherited risk for most autoimmune disease is often attributable to one gene loci.
False. It is attributed to multiple gene loci.
Why can infections trigger autoimmunity?
Infections may activate self-reactive lymphocytes that induce a local innate immune response increases costimulators and cytokines that may interact with self-antigens.
What is molecular mimicry?
The theoretical possibility that sequence similarities between foreign and self-peptide are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides.
T or F: Molecular mimicry is when the immune system attacks self-antigens due to a similarity between foreign peptides and self-peptides.
True
T or F: The management strategy of
the individual with an autoimmune disorder is
determined by a combination of
patient-related and disease-related factors.
True
What are the possible treatment options of autoimmune disease?
- Modification of the causative factors
- Immunosuppressive therapy directed at the immune response
- Management of disease related complication and symptoms.
What are the 4 examples of immunosuppressive therapy directed at autoimmune disease?
Corticosteroids
Chemotherapy with immunosuppressive effects (methotrexate)
Interferon type I
Monoclonal antibodies targeting mediator of the immune response
What do corticosteroids do?
They suppress the inflammatory response
What is Hashimoto’s Thyroiditis?
This is an autoimmune disease caused by lymphocyte infiltration into the thyroid gland leading to tissue destruction.
What are the symptoms of Hashimoto’s?
Fatigue, cold sensitivity, constipation, hair loss, weight gain, and depression
How is Hashimoto’s treated?
Replacement of thyroid hormone
What is anti-glomerular basement membrane disease?
This is when self-antibodies bind collagen of the basement membrane in the kidneys and the lungs and cause rapid glomerulonephritis and/or pulmonary hemorrhage.
What is the main histopathology behind anti-glomerular basement membrane disease?
Complement-mediated damage
How is anti-glomerular basement membrane disease treated?
It is treated with plasmapheresis to remove the auto-antibodies mainly. THe respiratory symptoms are managed with oxygen and kidney dysfunction is also managed.
What is systemic lupus erythematosus (SLE)?
This is a chronic inflammatory disease involving autoantibodies specific for apoptotic and necrotic cell debris, antibody and complement-fixing immune depositions and inflammation.
What are the non-pharmacological ways to manage lupus?
Minimize sunlight, stop smoking, and social support
What is the pharmacologic management of lupus?
NSAIDs for symptom management
Corticosteroids for immunosuppression
B cell targeted therapy for immunomodulatory effects
What is multiple sclerosis?
This is a T cell mediated autoimmune disease against the myelin in the white matter of the brain and spinal cord. Tissue damage results when T cell recognize and destroy the myelin.
What are the two main approaches for treatment in those with multiple sclerosis?
- disease modifying agents
- therapies for disease complications
What are the genetics behind autoinflammatory diseases?
Mutations in germline encodes elements of innate immune system. More monogenci than polygenic.
What does allogenic mean?
Taken from different individuals of the same species
What does autologous mean?
Taken for the individual’s own tissues, cells, or DNA
What is a xenograft?
Grafts between members of different species
What is an autograft?
Grafts from one part of the body to another in the same person
What is an isograft?
Grafts between genetically identical people
What is an allograft?
Grafts between members of the same species that differ genetically
T or F: The immune response seen in solid organ transplant does not depend on the type of organ being transplanted.
False. it does depend on the type of organ
_____________ play a critical role in allograft rejection.
Lymphocytes
T or F: The immune response for allograft organ rejection involves only one arm of the adaptive immune system.
False. It involves both arms
In solid organ transplant, what are the 4 main potential sources for an immune response?
ABO blood group antigens
Mismatched HLA antigens
Minor histocompatibility antigens
Non-HLA self antigens
What are the 2 phases of organ rejection?
- Sensitization
- Effector stage
What is the sensitization stage in organ rejection?
T cells recognize the alloantigens expressed on the cells of the foreign graft.
What is the effector stage in organ rejection?
Activated recipient immune cells infiltrate the organ and damage the tissue. This injury induces a nonspecific inflammatory immune response leading to apoptosis and natural kill cell use.
What portion of innate immunity plays a role in organ rejection?
Proinflammatory mediators
How are transplant rejections classified?
Immunologic and timing classification
What is the immunologic classification of transplant rejections?
Antibody-mediated rejection
T cell mediated rejection
Combination of cellular and antibody mediated rejection
What are the timing classification of transplant rejections?
Hyperacute (minutes after transplant)
Acute (in 6 months)
Chronic
What is the mechanism behind a hyperacute organ rejection?
Humoral mediated.
What is the mechanism behind acute organ rejection?
Cellular or humoral mediated
What are the strategies used to minimize transplant rejection?
- Assessment and optimization of donor-recipient compatibility
- Developing partial immunological tolerance
- Immunosuppressive drugs
- Management of rejection
What is the process of desensitization in solid organ transplant?
Treatment with immunomodulating therapies to reduce the levels of anti-HLA antibodies prior to transplant. This is done via plasmapheresis or drug therapies.
What were the 3 discussed drugs used a immunosuppressants prior to solid organ transplant?
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- Belatacept
- Corticosteriods
What is the MOA of calcineurin inhibitors like cyclosporine and tacrolimus?
They suppress the activation of T lymphocytes by inhibiting the production of cytokines. It impacts cell-mediated immunity more than humoral immunity.
What are the two common side effects of calcineurin inhibitors?
Nephrotoxicity and hypertension
What are the effects of corticosteroids?
It is an immunosuppressive and anti-inflammatory drug
What are the main side effects of corticosteroid use?
Hyperglycemia and HPA suppression
T or F: Corticosteroids should not be abruptly
discontinued when used for a prolonged time
True. Need to taper down so adrenal can begin to make their own cortisol again.
What are the two main complication of immunosuppressive therapies?
Cancer and infection
What are the strategies used to manage infection in solid organ transplant?
Immunization before
Prophylaxis anti-infectives
Management of active infections
T or F: Risk of malignancy (cancer) is 1-2x higher in transplant patients compared to the general population.
False. It is 3-5x higher
T or F: There is a large risk of bone fractures following solid organ transplant.
True
Are CD34+ cells and hematopoietic stem cells the same thing?
Yes!
What is a hematopoietic stem cell transplant?
This is the process where normal hematopoiesis and/or lymphopoiesis is established by the infusion of ex-vivo pluripotent stem cells
Why is stem cell transplant used?
- Eliminate the abnormal system and replace with normal functioning cells
- Rescue the bone marrow following high dose chemo or radiation
- Initiate graft vs tumor effect
How can stem cell transplant be classified?
Donor source of stem cell
Anatomic source of stem cell from donor
Strategy of preparing the patient to receive the HSCT
What is an allogenic donor source?
Patient receives stem cells collected from a donor that is HLA-matched
What is an autologous donor source?
Patient receives their own stem cells
What is a syngeneic donor source?
Patient receives stem cells from and identical twin
Out of an allogenic, autologous, and syngeneic donor source, which recipient would need immunosuppression before hand?
Only the allogeneic recipient
What are the 3 sources of stem cells?
Bone marrow
Peripheral blood
Umbilical cord
What are the two strategies used for the preparative regiment for stem cell transplant to suppress the immune system?
Myeloablative chemo and non-myeloablative chemo
What is engraftment syndrome in stem cell transplant?
The blood cells begin to proliferate but too many neutrophils were made. They produce a bunch of pro-inflammatory cytokines leading to capillary leak syndrome.
What is the treatment for engraftment syndrome in stem cell transplant?
Corticosteriods
Do you see engraftment syndrome in solid organ transplant?
No
What is Graft versus Host Disease?
This is when donor T-lymphocytes react against antigens on the host tissues. It is the leading causes of death in allogenic stem cell transplants.
What are the main organs affected by acute graft versus host disease?
skin, liver, and gut
What is the common manifestation of graft versus host disease?
Diffuse rash
What are the main medications used to prevent graft versus host disease?
Calcineurin inhibitors like tacrolimus or cyclosporine.
What are the most common complication following an allogenic stem cell transplant?
Graft versus host disease
Graft versus disease
Immunosuppression
Complications of immunosupression
What is the graft versus malignancy effect?
This is when donor T cells have been shown to have anti-cancer effects for recipients of hematopoietic stem cell transplants.
What is immunosurveillance?
This is the process in which the immune system looks for and recognizes foreign pathogens. These can include bacteria, viruses, and cancer cells.
What is the cancer-immunity cycle?
- Release of cancer cell antigens when a cancer cell dies at the hands of an APC
- Cancer antigen is presented
- T cells are primed and activated now
- T cells are trafficked to tumor site
- T cells infiltration tumor
- Cancer cells are recognized by T cell
- Cancer cells are killed
What is White Blood Cell Growth Factor?
It is a cytokine used to mobilize hematopoietic stem cells for hematopoietic stem cell transplantation and to help increase white blood cells used after chemotherapy
What is interleukin-2 ?
It is a cytokine used in cancer treatment
T or F: Aldesleukin (interleukin-2) administration is associated with cytokine stimulation and capillary leak syndrome.
True
T or F: monoclonal antibodies can be used to target cancer cell surface proteins (and/or their ligands) to inhibit the downstream
pathways initiated by the protein.
True
T or F: modifications of monoclonal antibodies can be done to increase efficacy in targeting the immune response.
True
What are antibody-drug conjugates composed of?
Antibody
Linker
Toxic payload
What are bispecific proteins?
Antibodies that can target two different things
T or F: All bispecific antibodies are bispecific T cell engager
False
What is a bispecific T cell engager?
It is a bispecific antibody that targets both the cancer cell and engage the T cell.
What is the main side effect of bispecific T cell engagers?
Cytokine release syndrome
T or F: Immune checkpoints regulate the activation and inhibition of T cells
True
T or F: Immune-related adverse events (irAE) can affect most tissues and organs. Immune-related adverse events can occur at any time during and following therapy.
True
What are CAR T cells?
These are genetically modified T cells changed to add a receptor called chimeric antigen receptor (CAR). This allows the T cell to better recognize cancer.
What is the main side effect of CAR T cell therapy?
Cytokine release syndrome
What are TCR T cells?
Genetically engineered T cell that
recognizes a tumor-specific, MHC bound mutation-derived proteins
(including intracellular targets)
What is the main side effect of TCR T cell therapy?
Cytokine release syndrome
What are tumor-infiltrating lymphocytes (TILs)?
TILs are a cellular strategy that uses the patient’s own tumor infiltrated lymphocytes to fight cancer
