Immunology-based therapies of diseases

Question 1

What is the difference between transplantation and transfusion?

Answer 1

• Transplantation is the transfer of tissue/organ from one individual to another
  o One type of transplantation is transfusion, which involves blood cells/blood products

Question 2

What are the primary immunological barriers to transplantation?

Answer 2

• Polymorphisms in protein-coding genes are the primary immunologic barriers to transplantation
  o Polymorphisms are different amino acids in a protein
  o Polymorphisms can cause immune responses

Question 3

What is an allogeneic immune response and what can it cause?

Answer 3

o Allogeneic immune response- a response to a difference in a polymorphism between two proteins
 Can cause inflammation and lead to injury/death of transplanted organ
* This is transplant rejection

Question 4

What protein is the most important determinant of an allogeneic immune response?

Answer 4

• MHC (HLA) proteins are the most important determinants of an allogeneic immune response- major barrier to transplantation
  o These are the most polymorphic genes in our body

Question 5

What proteins do class II MHC proteins have?

Answer 5

 Class II MHC has DP, DQ and DR proteins

Question 6

What proteins do class I MHC molecules have?

Answer 6

 Class I has A, B and C proteins

Question 7

Why is it so important to know blood types and what can happen if the wrong blood type is given? Describe each blood type

Answer 7

• Blood cells have carbohydrate antigens on their surfaces- these are the antigens that determine ABO blood type
  o Individuals can have pre-formed natural IgM antibodies that are specific for the A and B blood group antigens
   A blood type has anti-B antibodies and vice-versa
   O has both anti-A and anti-B antibodies
   A/B has neither
  o These natural antibodies can cause transfusion reactions through IgM-mediated responses such as complement activation and opsonization

Question 8

How can immune responses to transplanted tissues be avoided or minimized?

Answer 8

• Immune responses to transplanted tissues can be avoided by minimizing differences between individuals
• Transplant patients are typically treated with immunosuppressive drugs that can block T cell activation or kill lymphocytes
• For blood transfusions, blood typing is used to match the donor and the recipient
• Cross-matching can be used to test whether there will be a reaction between donor and recipient

Question 9

What is HLA matching and which proteins are the most important to match?

Answer 9

• HLA matching is used to reduce the risk of transplant rejection
  o HLA A, B and DR are the most important to match

Question 10

What are immunosuppressive drugs used to block T cell activation or kill lymphocytes? Describe their mechanisms of actions

Answer 10

o Calcineurin inhibitors (of which cyclosporin is the most common) blocks T cell response to antigen
o When the T cell is activated by the alloantigen, it will make growth factors (such as IL-2) which binds to receptor which signals T cell-> drugs that block this signalling include rapamycin
o Antibodies that bind to molecules on activated T cells and lead to their death-> called lymphocyte depleting antibodies

Question 11

What is cross-matching for transfusion and how is it done?

Answer 11

• Cross-matching can be used to test whether there will be a reaction between donor and recipient
  o Take the serum from the recipient to test for antibodies present in the serum
  o Take several different donors and test if there’s an immunological reaction (agglutination or death of cells in vitro)
   If there is agglutination or death of cells, not a good match

Question 12

What is passive immunotherapy? Why is it not used much?

Answer 12

• Passive immunotherapy:
  o Take a convalescent patient with antibodies against a disease and inject them into a patient that has the same sickness but that isn’t responding well
  o It is expensive and low throughput.

Question 13

What is vectored immunoprohylaxis and what is its advantage compared to passive immunity?

Answer 13

• Vectored immunoprohylaxis is the introduction of DNA encoding an antibody into individuals. This creates antibodies that could be protective against a microbe
  o Take protective antibodies from someone who has recovered from the disease-> clone the gefne for the antibody-> gene put in vector and transferred into individuals not responding well into their muscle cells-> antibody will get synthesised by the recipient
  o Relatively inexpensive

Question 14

What is chimeric antigen receptor (CAR) T cell therapy?

Answer 14

• Chimeric antigen receptor (CAR) T cells are created by introducing into T cells a DNA sequence that contains the recognition portion of an antibody fused to signalling components of the T cell receptor. CAR T cells have been used to treat some types of cancer
  o Can lead to formation of memory CAR T cells

Question 15

What are two broad methods are used to introduce genetic material from the immune system into individuals for therapeutic purposes?

Answer 15

• Vectored immunoprohylaxis
• Chimeric antigen receptor (CAR) T cells

Question 16

What are two new immunologic approaches to cancer therapy? Describe how they work

Answer 16

• Neoantigen discovery involves searching for antigens that uniquely occur in a tumor (due to mutations that are part of the tumorigenic process) and are capable of binding to host MHC
• Checkpoint blockade is the reactivation of existing T cells that are nonfunctional due to inhibitory signaling. This is accomplished by blocking inhibitory receptors, which rejuvenates exhausted T cells

Question 17

How is neoantigen discovery applied to patients for tumor treatment?

Answer 17

o Using NGS, can identify mutations in the tumor, find which of those mutations can bind to the host MHC molecule and then use those specific peptides to eliminate the tumor-> vaccination to activate T cells with cancer neoantigens
o Invles designing a patient-specific vaccine
 First the patient’s tumor and normal cells must be sequenced to reveal tumor-specific mutations
 Then the mutations that are most likely to create HLA-binding peptides are inferred with computational methods

Question 18

What is melanoma?

Answer 18

Cancer of melanocyte

Question 19

How does melanostic melanoma work and why is it so dangerous? How is it diagnosed internally?

Answer 19

• Melanoma- cancer of melanocyte
• Primary tumour- original site where cancer appears
• Primary tumour can expand at the local site, but cancer cells also migrate away from the primary tumour and find their way to other organs in the body- the process of cancer cells migrating to, becoming established in, and growing in other organs is known as metastasis
  o In melanoma patients, cells that have metastasized are often found in the lungs, liver and lymphatic centers
  o Radiographic methods, including CT scans, are often used to locate metastases in organs such as the brain, lung and liver
  o Left untreated metastatic melanoma can lead to organ failure and death

Question 20

Does chemotherapy perform well in melanoma?

Answer 20

No

Question 21

What were early therapies for metastatic melanoma?

Answer 21

 Interferon gamma and IL-2 are non-specific immunotherapies
 Interferon-alpha was also approved as a therapy: but gave patients flu-like syndrome

Question 22

What are side effects of PD-L1 therapy?

Answer 22

o No side effects except for pallor of the skin (vitiligo)/white patches on face, neck and hands 3-4 months after therapy
 Immune response elaborates more broadly from the melanoma which means normal melanocytes can also be attacked
o Can also have skin rash or diarrhea rarely
o 5% have autoimmune attacks of normal tissue which would need to be treated with corticosteroids
 This doesn’t eliminate the anti-tumour responses