[IMMUNOPHARMACOLOGY] July 15, 2013

Slide 2:

Immunopharmacology deals with the immune system by manipulating

or modulating it. It has a significant role in preventing the rejection of

grafts, which the body counts as foreign materials.

The role of immunopharmacology in such cases is to reduce or diminish

the immune system for specific periods of time.

It also has a role in autoimmune diseases, which is characterized by

hyper immunity. And another role in the cases of immunodeficiency like

in AIDS and cancer.

Interestingly, In cancer, the case is not specifically reduction of

immunity, but it is that the cancer cell evades the immune system of the

body.

Cancer patients are given cancer vaccines, and mediators such as :ILs ,

TNFα, and IFNγ, to enhance their immunity.

Slide3:

There are different types of rejection, the first one is hyper-acute, in

which the body rejects the organ directly as soon as it's transferred to

the patient, leading to clotting, in such cases the organ must be removed

from the patients body immediately.

Chronic rejection occurs in all cases of organ transplantation. The patient

might survive after that , or he might not be able to hold it after 4 to 5

years. In this case we give immunosuppressants only in the first year or

few months, but we cannot give them for life.

For instance, in the case of lung transplantation, the lung undergoes

fibrosis after 4-5 years, and it's the same for the kidney transplantation,

in such cases we do not use immunosuppressants to modulate the

immune system, as mentioned earlier, we only use them in the

beginning (when the rejection is counted acute).

[IMMUNOPHARMACOLOGY] July 15, 2013

In acute rejection, the immune response must be completely reduced,

by deleting the immune system completely for specific periods of time.

This is done at the level of the cellular response , the humeral response

might be involved sometimes, but the suppression is focused on the

cellular response (T-cells).

Slide 4:

Transplant rejection agents, or immunosuppression is a complex

process. Because the drugs that are given to the transplant patients are

very strong, and have many side effects. One important factor

contributing in its complexity is the narrow therapeutic index, which

means that the toxicity margin is close to the therapeutic margin.

This complexity will lead to low compliance, because the drugs cause

irritating side effects to the patient, so he might decide to stop the

administration of the drug at some point.

FYI: Compliance is A term used to describe how well a patient's behavior

follows medical advice as in talking with the patient about the goals of

the drug chosen.

Compliance is a remarkable issue in our society.

Those immunosuppressants increase the tendency to infections and

cancer , which is dangerous to the patients, since infections could lead to

death.

slide 5:

Glucocorticoids; known as cortisol, the magical drug.

Calcineurin inhibitors; Calcineurin is a substance released once the

complex between the T cell and the Antigen presenting cell occurs and it

(calcineurin) activates other pathways that release Interleukins.

There's an easy way to decrease immunity, which is killing T and B cells .

We give drugs like cancer drugs that are selective towards the immune

system at low doses which target these cells.

[IMMUNOPHARMACOLOGY] July 15, 2013

m -Tor inhibitors: are related to the cell cycle. Once we inhibit m Tor, the

cell cycle is reduced and as a consequence activation of T cells is

reduced.

* IL-2 activation leads to a cell cycle activation, we need to decrease the

production of IL-2, to prevent the immune response. Another way is

blocking IL-2 receptor in order to inhibit the cell cycle.

Glucocorticoids suppress production and release of IL-2,1,10, TNF-α .

To be more clear, we are interested in cellular mediated immunity more

than humoral, Because the cellular immunity is responsible for

transplant rejection most of the time. However, there is a strong relation

with the humoral response but, when we decrease cellular mediated

pathway, we decrease severe exacerbation and harshness.

Slide 6,7:

Steroids cross the cell membrane and attach to intracellular receptor,

then they enter the nucleus and inhibit the transcription of a certain

gene. So, Cortisol will enter the cell and bind to its receptor, then attach

to the promoter region inhibiting transcription of IL-1, IL-2, TNF-α , IFN-

gamma, which are the mediators that activate T cells.

Between the previous mediators, the most important one is IL-2, for it's

responsible for re-stimulations to the same cells so we need it inhibited.

(Some books say steroids inhibit IL-1 more , but the doctor insisted it's

IL-2.)

[IMMUNOPHARMACOLOGY] July 15, 2013

Regardless of which substance is being inhibited, T cell number will

decrease. Will B cells be affected? Yes , they will as mentioned in the

slides.

Another effect for steroids, Anti-inflammatory effect; immune response

is inflammation which is mediated by IL-2 and others. So, inhibiting

production of those substances will lead to an anti-inflammatory effect.

Steroids' anti-inflammatory effect will be used in many cases: most

importantly in Asthma, Psoriasis (صدفية) , Rheumatic Arthritis. No

complete inhibition for immune response will happen, but only

inflammation reduction.

*The dose of the drugs is different for different diseases and for

different cases.

Slide 8:

Clinically, Glucocorticoid is used for Rheumatoid arthritis, which is as we

know a disease in which the immune cells attack the joints. It's also used

in another disease called idiopathic thrombocytopenic purpura; which's

characterized by red spots on the skin as a result of inner bleeding and

reduced coagulation, a result of reduction of circulating platelets, why?

They're being attacked by body's immune cells, so we need

immunosuppression. It is an autoimmune disease either chronic or acute

but in both cases, treatment is steroids.

Glucocorticoid is also used in the cases of blood transfusion as a

prophylactic agent. And before transplantation surgeries, it's given in

large amounts, then the administration continues for an entire year after

the surgery.

Notice that in cases of auto-immunity we always Decrease the

immunity.

[IMMUNOPHARMACOLOGY] July 15, 2013

PS: A drug called warfarin could cause reduced coagulation and red spots too.

The doctor mentioned an example of a drug called Rhinocort, a short or

long acting corticosteroid, nasally inhaled as an aerosol, decreases

inflammation, it's not an immunosuppressant but decreases allergic

reaction and used in the long acting treatment for people with allergy.

Slide 9 :

- Fat redistribution : moon face and buffalo hump.

- Adrenal gland suppression, also known as adrenal crisis, occurs if the

patient stops the administration of glucocorticoid suddenly after taking

it for more than 1 month. To prevent that, the patient must decrease

the dose gradually (tapering doses).

*FYI: if cortisol was taken for 2-3 weeks, there would be no problem to

stop the administration suddenly. ( no need for tapering dose)

- Psychosis means personality changes .

- One more side effect is hypertension.

- Doses that are given for autoimmune patients like asthma , psoriasis will

not lead to growth failure or delayed puberty will not happen. That's

why some patients hesitate to take cortisol because they fear such effect

which is known as cortisol phobia.

-

Slide 10:

Those drugs inhibit reactivation of T cells and reactivation of the cell

cycle and mitosis of T cells.

Cyclosporine and Tacrolimus will work on Calcineurin, Sirolimus will

work on m-TOR (which is induced by IL receptor).

Graft versus host disease, is caused by the T-cells which remain in the

tissue graft, those T-cells attack the recipients body. This is fixed by

treating the donor first, which is done by decreasing the immune cells in

the donor.

Slide 11:

[IMMUNOPHARMACOLOGY] July 15, 2013

We need drugs that act as an Anti CD3, or Anti CD 28.

The whole story revolves around the fact that we don’t want T cell

number to increase.

Slide 12:

Cytochrome P450 which is related to drug metabolism can result in

either reduction only, or inhibition. But what results in such reduction

and inhibition?

Conflicts with other drugs or certain kinds of food. Cyp4503A4

metabolizes cyclosporine, so other drugs might reduce or inhibit Cyp,

this will affect the concentration and metabolism of cyclosporine.

The grapefruit or citrus fruit in general inhibit Cyp450 which increase the

concentration of cyclosporine and tacrolimus.

*Cyp450 varies between individuals, a form of polymorphism.

Those drugs have narrow therapeutic window; a high dose immediately

leads to toxicity>>> TD50/ED50; the higher the number, the wider the

therapeutic window. (Antibiotics have wide therapeutic window)

Monitoring Parameters: drugs at the hospital have monitoring

parameters which means we have to monitor the drugs; trough and

peak levels, liver function, renal function because the drugs' metabolism

is affected genetically from a person to person.

the last two minutes of the record aren't clear, please refer to slide #14

and to the record.

Lubna Abu-Alenain

[IMMUNOPHARMACOLOGY] July 15, 2013