Immunosuppression (Concepts)

Question 1

What is the process following T cell receptor activation leading to synthesis of IL-2?

Answer 1

1. Binding of TCR to MHC-Antigen complex in presence of appropriate co-receptors.
2. Activation of Ca²⁺ channels resulting in ↑[Ca²⁺]_i.
3. Activation of calcineurin (CaN), causing dephosphorylation of NF-AT.
4. Dephosphorylation allows it to transit into nucleus, where it binds to promoter regions of DNA to stimulate expression of IL-2.

Question 2

What are the different types of IgG receptors present?

Answer 2

1. FcγR1 → Neutrophils → Phagocytosis
2. FcγRII → Macrophages → Phagocytosis
3. FcγRIII → NK cells → ADCC

Question 3

What is a chimeric mAb?

Answer 3

Human constant domains + Murine variable domains

Question 4

What is a humanised mAb?

Answer 4

Human Ab + Murine CDR

Question 5

Why does the presence of human Fc regions increase life-span of mAb?

Answer 5

Allows binding to FcRn on endothelial cells and recycling

Question 6

How do FcRns mediate recycling of mAbs?

Answer 6

1. Antigen-mAb complex binds to FcRn and is pinocytosed into endothelial cells
2. In endosome, bound antigen broken down but the mAb is unaffected and is released back into bloodstream

Question 7

What is the nomenclature associated with mAbs?

Answer 7

Chimeric = -ximab

Rat/mouse hybrid = -axomab

Humanised = -zumab

Human = -umab

Question 8

How can mAbs be used to improve NK cell function?

Answer 8

• Most IgGs are fucosylated, reducing its affinity for FcγRIII on NK cells.
• mAbs can be engineered to be afucosylated, increasing its affiinity for FcγRIII and thus ADCC.