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Immunology and Virology > Indiscriminatory Immune System 3 > Flashcards

Indiscriminatory Immune System 3 Flashcards

Immune System and Treatment

1
Q

Immunisation and Vaccination

A

Single infection usually sufficient to generate protective immunity to a pathogen - prompted practice of variolation against small pox

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2
Q

Two types of immunisation

A

active immunity: usually permanent, protection produced by persons own immune system
passive: temporary protection that changes with time, protection transferred from another person/ animal

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3
Q

Immunoprophylaxis

A

Performed before expsoure ( or soon after exposure in certain cases) to an infectious agent to prevent infection

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4
Q

Immunotherapy

A

performed during active infection ( or existing cancer) intending to cure infection (or cancer)

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5
Q

Features of effective vaccine

A
  1. (Safe): must not cause illness or death - low level of toxicity is not acceptable as it will be given to large number of people.
  2. Protective immunity
  3. Give long lasting immunity which last for several years - impracticable to give large/ dispersed rural populations regular booster vaccinations - B and T lymphocytes must be primed by the vaccine.
  4. Induce neutralising antibodies - cheap if they’re administered to large population.
    Induce protective T cells
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6
Q

Practical considerations of a vaccine

A

Low cost - vaccines are the most effective measure in health care but this benefit is eroded as the cost-per-dose rises.
Biological stability
Ease of administration
Few side effects

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7
Q

Other vaccinations/Components - Booster shots

A

Booster Shots: same vaccine given at a later date (e.g. diphtheria and tetanus toxoids (DT) given every 10 years to refresh the memory cell population

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8
Q

Other vaccinations/Components - Adjuvant

A

Any substance that enhances the immunogenicity of substances mixed with it.
Differ from protein carriers in that they do not form stable linkages with the immunogen.

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9
Q

Safety and efficacy of replicating (live attenuated) and non-replicating vaccine approaches

A

live-attenuated viruses are some of the most effacious (e.g small pox) but have the most risk as they are replication-competent. non-replication competent viruses considered to be safer.

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10
Q

examples of live-attenuated viruses

A

measles, mumps, and rubella vaccines,

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11
Q

non-replication competent vaccines

A

hepatitis B (subunit) HPV (virus like particle), inactivated poliovirus vaccine (inactivated virus), numerous AIDS vaccine candiates using non-replicating strategies.

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12
Q

Different vaccine platforms (used for SARS-CoV-2 vaccine)

A

Inactivated vaccines: contain SARS-CoV-2 thats grown in cell culture and chemically inactivated
Live attenuated vaccines: made of genetically weakened versions of SARS-CoV-2 thats grown inc ell culture
Recombinant spike-protein-based vaccines.
Recombinant RDB-based vaccines
Viral like particles. (VLP): carry no genome but display the spike protein on their surface.
Replication-incompetent vector: vaccines cannot propagate in the cells of the vaccinated individual but express the spike protein within them.
Replication-competent vector: vaccines propagate to some extent in the cells of the vaccinated individual and express the spike protein within them.
Inactivated virus vector vaccines: carry copies of spike protein on their surface but has been chemically inactivated.
DNA vaccines consist of plasmid DNA encoding the spike gene under a mammalian promoter.
RNA vaccines consist of RNA encoding the spike protein and are typically packages in LNPs.

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13
Q

Immunotherapy

A

Form of therapy targeting the imune system to help infection, allergy, autoimmunity and cancer

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14
Q

Uses of immunotherapy

A

-Inhibit unwanted or excessive immune response-allergy & autoimmunity
-Enhance immune responses-cancer
-Switch off immune undesired responses-transplantation

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15
Q

Immune cel

A

Immune cells within tumours predict overall survival. T-cell infiltration within tumours predict overal survival in multiple cancer types..?

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16
Q

Chimeric Antigen Receptor (used in adoptive t cell therapy?)

A

CAR made of antigen binding domain of BCR and signalling domain of the TCR.
A Viral vector used to transfect T cells with CAR gene.
CAR expressed on the surface of T cells after successful transduction.

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17
Q

Process of Adoptive T cell therapy

A
  • Leukocytes are generally collected by leukapheresis and lymphocytes can be enriched by counterflow centrifugal elutriation or subsets selected.
  • Enriched lymphocytes placed into culture and stimulated with bead-based artificial antigen presenting cells and viral vector added.
  • Culture is expanded in a bioreactor for several days
    T cell bulk product is washed and concentrated,
    samples removed for quality control release testing and quality assurance review.
  • Final formulation is cryopreserved allowing facile shipment to distant infusion sites
  • Final product bag is thawed and infused.
  • Manufacturing time is generally 5 to 10 days, and collection to infusion times can range from 2 to 4 weeks depending on patient clinical status and chemotherapy conditioning regimens.
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18
Q

Process of CAR T-cell manufacturing(used in adoptive t cell therapy?)

A

Apheresis: Collect patients white blood cells.
Manufacturing Process: Isolate and activate T cells, Engineer T cells with CAR or T-cell receptor gene, Grow and expand number of T cells.
Infusion: Infuse patient with engineered T cells.
Vein to vein time averaged in 17 days in clinical trials.

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19
Q

Generations of CARTs

A

Fourth generation of CARTs (also called TRUCKS) based off second gen with an additional gene cassette that induces cytokine expression.
contains scFv (single-chain variable fragment) and NFAT (nuclear factor of activated Tcells).

20
Q

Ideal CAR-T target Properties

A

Tumour specific
Universally expressed on tumour cells only
Cell surface molecule

21
Q

why is CD19 an ideal CAR-T taget?
Name some other ideal targets

A

CD19 found on B cell malignancies (NHL,CLL,ALL ect). Expressed only on early B cells but not stem cells.
other targets: BCMA, GPRC5D

22
Q

Why is GPRC5D an ideal CAR-T target?

A

GPRC5D: orphan G protein-coupled receptor, class C group 5 member D.
normally only expressed in the follicle.
Previously identified as expressed by mRNA in marrow aspirates from patients with MM - but confirmation of protein expression remained elusive.
determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples witha distrbution similar to BCMA using quantitative immunoflouresence.

23
Q

Advantages of CAR-T cell therapy

A

HLA-independent recognition&raquo_space;» Universal application.
Active in both CD4 or CD8 T cells
Target Antigens include proteins, CHO, and glycolipids
Rapid generation of tumour specific T cells
Minimal risk of autoimmunity or GVHD
A living drug with single infusion

24
Q

CAR-T cells for refractory SLE

A

https://www.nejm.org/doi/10.1056/NEJMc2107725

25
Q

Cytokines for monotherapy - IL-2

A

-IL-2: 1998 FDA approved for Melanoma, effective in low doses to produce T cells non-specific expansion, Side Effects: “Capillary leak syndrome”, Tregs expansion.

26
Q

Cytokines for monotherapy - IFN-a and IFN-g

A
  • IFN-a: First cytokine approved by FDA. multiple action, increase antigen presentation and promotes all immune cells activity and proliferation as Macrophages, DCs, NK and T cells. Cons: Autoimmunity and local psoriasis.
  • IFN-g: IFN-γ enhances MHC class I and II expression in dendritic cells and mononuclear phagocytes, as well as the production of IL-12 by dendritic cells. In B cells, IFN-γ stimulates survival and growth in both mouse and human cells, and redirects B cells from proliferation towards differentiation. IFN-γ favours the development of Th1 vs Th2 cells and stimulates monocyte differentiation and function
27
Q

Why are cytokines ( and monoclonal anitbiodies..?)used as a monotherapy?

A

not everyone can be directly protected with vaccines
– some people are unresponsive to them or have allergies or health conditions that prevent them from taking them..???

28
Q

Other cytokines used for monotherapy

A

GM-CSF, IL-10, -12, -15, -21 & TNF-a

29
Q

Cytokines : Immunomodulatory imide drugs (IMiDs)

A

special group of drugs with a spectrum of immunotherapeutic potential
Stimulate T cells and NK cells while inhibiting TNF and IL-6 production

30
Q

Examples of IMiDs

A

Thalidomide and its analoguesas (2nd generation) Lenalidomide and 3rd generation: Apremilast (PDE4 inhibitor).

31
Q

Cytokines in combination therapies

A

-CTLA-4 and PD1 inhibitors combination.
-nivolumab and
ipilimumab approved for melanoma.
-bevacizumab and IFNα&raquo_space; FDA in RCC (FDA).

32
Q

Immunotherapy: Interferon Beta Therapy

A

Done via injections

33
Q

What does interferon-B do?

A

Alert other cells of viral infection.
Balances inflammatory agents in the brain
produces nervse growth factor
increases survial time
DOES NOT directly combat viruses or change the mortality of the infected.
Some viruses are able to suppress interfereon-B production in cells.

34
Q

What are biologics?

A

A new class of therapeutic monoclonal antibodies. These are compounds.

35
Q

What natural proteins/ cells are compounded with monoclonal antibodies for biologics?

A

anti-lymphocyte globulin, cytokines, and fragments of proteins.
Also (also compounded with this??)the use of whole cells, as in the adoptive transfer of T cells in cancer immunotherapy

36
Q

Difference betwen Chimeric Antibodies and Humanised antibodies.

A

Chimeric antibodies: Has murine Fv and human Fc regions. Human anti-chimeric antibodies still observed.
Humanised antibodies: Murine CDRs +human framework and Fc.

37
Q

What are humanized antibodies?

A

Humanised antibodies are murine antibodies that are humanised by grafting their CDRs onto the variable light and heavy frameworks of human immunoglobulin molecules whilst retaining the murine framework residues needed for the integrity of the antigen.

38
Q

Targeting of immune checkpoints (basically the targeting of co-inhibitory signallers)

A

Ipilimumab (anti-CTLA-4)&raquo_space;> Significant toxicities
Pembrolizumab and nivolumab (anti-PD-1)
Atezolizomab & Daratumumab (anti-PD-L1)&raquo_space; Less toxic

39
Q

Monoclonal antibodies used as therapy - types and what they treat.

A

Anti-TNF-alpha: inflammatory bowel disease and rheumatoid arthritis: inhibits inflammatory actions of TNF-alpha.
Anti-CD20: non-Hodgkin’s lymphoma: ADCC destruction of B cells.
Anti-lymphocyte globulin: treatment of acute graft rejection: depletes T cells via ADCC or inhibits of cell function.

40
Q

Mechanisms of action of monoclonal antibodies used as therapy

A
  1. Blocking action of molecular targets
    -Can work antagonistically by binding a receptor to prevent activation
    -Can also bind the antigen and prevent activation
    2 “Magic Bullet”
    -Compound with target specificity is coupled with various effector groups
    - Toxins, radionuclei, enzymes, DNA
    3 Signal molecules
    Coupled to mediators of apoptosis, cell division, etc.
41
Q

Rheumatoid Arthritis Symptoms

A

Chronic, autoimmune disease characterized by:
Severe joint inflammation
Increased synovial fluid and thickened synovial membrane
Destruction of bone and cartilage in several joints
Elevated levels of pro-inflammatory cytokines
TNF-α, IL-1, IL-6
Affects 1% of the US population
Women are 3 times more likely to develop
If untreated for 2+ more years, irreversible damage occurs

42
Q

Treating Rheumatoid Arthritis: Infliximab

A

Remicade® by Johnson & Johnson
Chimeric mAb
Anti TNF-α
Approved by the FDA in 1998
Administered intravenously
Designated for use in patients who did not respond to methotrexate
Proven to slow the clinical and radiological progression of rheumatoid arthritis

43
Q

RITUXIMAB (Rituxan)

A

-Therapeutic chimeric anti-CD20 monoclonal antibody with mouse variable and human constant regions.
-Contains the human IgG1 and murine variable regions that target CD20 B-cell antigen.
-Binding Rituximab to CD20 causes apoptosis of B cells.

44
Q

What can RITUXIMAB treat?

A

-Response rates of 50% to 70% in follicular lymphomas.
-Response rates of 90% to 100% when used in combination with various chemotherpay procedures.
-Concluded that the dose of 4, once-weekly 375 mg/m squared IV infusions of Rituximab was safe and effective in patients with relapse or refractory B non-Hodgkin’s lymphoma

45
Q

Toxic effects of rituximab

A

-Short-lived mild reactions to infusion ater first treatment: fever, chills, rigors, rash and nausea.
-Can also cause cytotoxicity?

46
Q

Immunosuppressive agents and what they target

A
  • Corticosteroids (block cellular infiltration, cytokine release, T cell maturation, etc.)
  • Azathioprine (inhibit lymphocyte proliferation)
    -Cyclosporine (inhibit IL-2 gene expression; Decreases proliferation and differentiation of T cells)

-Anti-lymphocyte serum (causes lymphocyte destruction and removal)

-Anti-CD3 (causes T cell destruction)

-Anti-CD4 (causes T cell destruction

-Cytotoxic drugs and ionizing radiation (block cell proliferation, lymphopoiesis)

47
Q

Mesenchymal stem cells as immunotherapy

A

Proposed for treatment of steroid-resistance graft vs host disease.
Potenital mechanisms of MScs interactins with immune cells…
https://pubmed.ncbi.nlm.nih.gov/18468541/

Immunology and Virology (7 decks)

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