Components of Immune System:

T-cells

Lymphatic vessels, lymph nodes

Bone marow cells

Activated T cells generated effector Th1 & Th2

Th1: Cell mediated immunity involved in killing all foreign cells

Th2: Humoral immunity, stimulate B cells to produce antibody that are specific to antigen

Stimulators of the Immune system

IL-2

GM-CSF

Interferon

Why we suppress the immune system?

 1, prevent rejection of organ transplant

2, treat autoimmune disorder

3, prevent Rh hemolytic disease of the new born

Organ Transplants

Autografts: your own tissue or identical twin

Allografts: from some1 else

Xenografts: from animal tissue

Diff rejection rxn

Hyperacute: fast, due to pre-existing antibody

Acute: days to months, main barrier to allograft, we need to block T-cell recognition of that foreign tissue

Chronic: years battle of transplant rejection

The major component with rejection response is T-cell recognition of transplant as foreign.

HLA antigens must be as similar as possible between the donor and recipient.

Autoimmune Disorders

eg: rheumatoid arthritis

type 1 diabetes

Gender difference, women are more prone to autoimmune disease.

Rh hemolytic disease of newborn

Mother is Rh-

Baby Rh +

mother produce antibody against Rh antigen for second baby

Drugs Targets

1, Cell proliferation (low selectivity)

2, T-cell function (more focused, less toxic)

3, antibody approaches: antigen recognition (high selectivity)

-Corticosteroids (predisone)

1, ↑expression of anti-inflammatory protein genes

2, ↓ expression of inflammatory protein genes (IL-1, IL-2)

3, ↓#of lymphocytes by increaseing migration to extravascular spaces

4, high dose can kill immune cells by apoptosis

Cytotoxic drugs

Cyclophosphamide alkylates DNA

Azathioprine fake purine nucleotide analog.

Mycophenolate mofetil (MMF) blocks de novo purine synthesis, inhibit T-cell, B cell Ab production

Methotrexate folate analog

T-cell Targets-Calcineurin inhibitiors

Cyclosporine & Tacrolimus

they inhibit calcineurin, inhibits NFAT binding

thus inhibits IL-2 production in activated T-cell. 

When you decrease IL-2 production, you decrease IL-2 receptor as well.

Rapamycin (Sirolimus)

blocks the effectiveness of IL-2 by blocking steps in singal transduction pathway for proliferation in T-cells

Antibodies

make antibody bind to IL-2, inhibit IL-2's ability to interact with IL-2 receptors

or

make an antibody to block IL-2 receptors

Polyclonal antibodies (non-specific)

Anti-lymphocyte globulin (ALG)

Anti-thymocyte globulin (ATG)

cause rapid depletion of perippheral lymphocytes to prevent hyperacute phase of graft rejection.

Monoclonal & Humanized antibodies

(specific)

Murine monoclonal antibodies

Chimeric monoclonal antibodies

Humanized monoclonal antibodies

OKT3 (muromonab)

murine monoclonal antibody, binds to T-cell CD3 and kills cytotoxic human T-cells.

used to reverse acute allograft rejection.

Infliximab

humanized anti-TNF antibody

binds to TNF-a and prevents it from reacting with its receptor which blocks the stimulation of macrophage

used for Crohn's disease and rheumatoid arthritis

TNF is one of the mediators of autoimmune disease

Daclizumab (monoclonal ab)

 it binds to alpha chain in IL-2 receptor (CD25)

blocking amplification of immune response for T-cell proliferation.

can be used with calcineurin inhibitors to prevent renal graft rejection.