10. Immune Regulation

8/2/2019 10. Immune Regulation

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Assoc. Prof. Ma. Jennifer R. Tiburcio,MSMTChair, Department of Med Tech

UST Faculty of Pharmacy



enhance

suppress

Immuneresponse



Immunoenhancement/Immunopotentiation

1. Increasing the rate at w/c the response occurs

2. Elevating its magnitude

3. Increasing the duration of the response



Nonspecific potentiators

Adjuvants(Substances that enhance the immunogenicity of

molecules without altering their chemical composition)

1. Increase the efficiency of the macrophage processingof antigen2. Prolonging the exposure to an antigen

3. Amplifying the proliferation of IC lymphocyte byenhancing lymphokine activity



Freund’s adjuvant

A classic adjuvant used in experimental animals

Emulsion of paraffin or mineral oil (usually Bayol F)Lanolin or Arlacel A is used as emulsifying agent

1. Incomplete Freund’s adjuvant (IFA) Water in oil w/ antigen

Increases humoral Ab response about 100-fold

Greatly reduced the required amount of antigenProlongs the phase of active Ig synthesis by months



2. Complete Freund’s adjuvant (CFA) An IFA plus mycobacteria /cell wall components

Markedly enhance both Ab & CMI

Ex. Elevated IgE – heat killed B. pertussis BCG – causes macrophage activation & enhances

NK cell activity



Class Mechanism of action Compound

Depot

Water-in-oil

Delays release of Ag

Prolongs lymphoid tissueexposure to antigen

Freund’s adjuvant

Precipitants Same as above Calcium alginate

Absorbents Same as above Alum, Aluminum

hydroxide, Bentonite,Polyacrylamide,Methylated BSA

Irritants Induce inflammatory response

w/c increases Ag exposure tomacrophage, T and B cells

Foreign bodies,

Mycobacteria (wax D)(muramyl dipeptide)

Mitogens Increase clonal expansion of Tand B cells during an immuneresponse

LPS, PHA, Con A



Class Mechanism of Action CompoundsLymphokines Enhance proliferation

and/or differentiation of Tand B cells

And macrophages

IL-1, 2 and 3

MAF

IFNs

Syntheticpolynucleotides

Stimulate Ag processingand T helper cell activity

Polyadenylate-uridylate



Specific potentiators

Helper factorsSecreted by T cells following interaction of

Ag specific receptor w/ its homologous epitopeTransfer factors

An Ag specific dialyzable extract of immune T cellsthat is capable of transferring CMIImmunogenic RNA

Extracted from the lymphoid tissues following Ag injectionAppears to be an Ag receptor complexed w/ cellular RNA

w/c greatly increases immunogenicity of a molecule



Immunosuppressionreduction in a large portion of immune responsiveness

A. Physical means

a. Surgical manipulation

1. Bursa of Fabricius & thymus

In neonatal period – immunologic competence not develop inthe corresponding cell line

After immunologic development, IC affected very little

2. Removal of peripheral lymphoid tissues – actual tissues removed

Lymph nodes & lymphoid cells in connective tissue – little effect

(too diffuse to be removed completely by surgical procedures)

Spleen does not grossly impair Ab production

b. Ionizing radiation damages the lymphoid organs & bone marrow



B. Chemical & Biologic means

a. Lympholytic agents

Can block the expression of the IR (cell lysis) but more effectivein disrupting the initiation of the IR

Types: ionizing radiation & Abs (ALS or ATS)

b. Lymphocytotoxic agents

1. Antimetabolites (purine & pyrimidine analogues & folic acidantagonists – methotrexate) interfere w/ DNA synthesis

2. Alkylating agents (cyclophosphamide) – interfere w/ cell division by altering guanine so DNA base pairing errors occur. Can crosslink the two DNA strands thus blocking replication



3. Antibiotics (cyclosporine) – suppress graft rejection reactions.Exerts an inhibitory effect on IL-2 action thus blocking the expansion

of the helper/inducer T cell population

4. Cortisone – immunosuppressive & inflammatory. Lympholytic in animals but not in humans – alter cell migration & cause lymphopenia & monocytopenia shortly after injection

c. Antibodies

1. Abs that react w/ lymphoid cells such as ALG or ALS particularlyantithymocyte induces immune deficiency in transplant patients bysuppression of CMI

2. Preformed Ab followed by injection of sp. antigen IR in the host willbe blocked. The injected Ab binds up the Ag & prevents its access tothe lymphoid tissue



3. If Abs that are specific for the Ag combining site (idiotype)-specifically abort that particular response

C. Immunosuppression associated with diseases

Congenital immunodeficiencies

Brutons agammaglobulinemia – failure of the development of theB Cell humoral immunity – Ab production – suffer from repeatedbacterial infection

DiGeorge syndrome – failure of the development of third & fourthpharyngeal pouches during embryogenesis – recurrent viraldiseases

MalignanciesLymphomas may disrupt normal lymphocyte functions directly or

may “crowd out” normal lymphocytes from bone marrow & peripherallymphoid tissues



Infections

Measles & certain viral diseases cause a transient depression in

CMIRHIV infection causes a profound IS w/c renders the host

susceptible to fatal infection caused by opportunistic pathogens

Malnutrition

CMI most sensitive to nutritional deprivation, HI, C’ and phagocyticfunctions are also affected



Tolerance

absence of specific immune responses in a fully competent

person

A. Naturally acquired (Autotolerance, neonatal ornatural tolerance)

Escape from this – autoimmune diseases

During fetal development, the ability to recognize one’s own

tissues is acquired.

Theories:

Clonal deletion theory

It is probable that clone of cells capable of responding to own tissues arise throughout life. These clones (forbidden clones)are immediately deleted by encountering an overwhelming amount of self antigens or by the activity of antigen-sp T suppressor cells



B. Immune tolerance

1. Gradation of tolerance

Partial – unable to respond to some of the epitopes on theAg but can respond to others

Immune deviation/split tolerance – one of the immune

responses can be interfered with, but not anotherEx. IgM response may be blocked but not IgG



2. Pathways to B cell tolerance

As an immature B cell matures into Ab forming cell it becomes resistant to tolerization. At the same time the form of Ag presentation w/c will produce tolerance varies. The type of tolerance induced is dependent on the maturity of the cell, the Ag and the manner in which the antigen is

presented to the cell

A. Clonal abortion

low concentrations of multivalent Ag may cause theimmature clone to abort



B. Clonal exhaustion

repeated antigenic challenge with T-independent Ag mayremove all mature B cell clones

C. Functional deletion

absence of T helper cell with the presence of T-dependentAgt or an excess of T-independent Ag prevents mature B cellfrom functioning normally

D. Antibody forming cell (AFC) blockade

high concentrations of T-dependent Ag are blockadingthe receptors of the cell thereby interfering Ab secretion



3. Pathways to T cell Tolerance

T cells do not show marked differences in their tolerizabiltiy. The Ag required to produce tolerance and in presentation is particular to each individual T cell subset.

A. Clonal abortion

immature T cell clones may be aborted in a similarmanner to B cells

B. Functional deletion

the subsets of mature T cells may be individually deletedleading to the loss of only one of the functions of the T cell group



C. T suppression

suppressor T cells actively suppress the actions of other

T cell subsets or B cells

T and B cells differ in their susceptibility to in vivotolerization with respectto the course of tolerance and also the

levels of antigen required to tolerize the cells



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10. Immune Regulation