2. Immunopotentiation
• The ability to potentiate the host immune
response to control chronic infections.
• 3 ways to potentiate.
• Vaccination, adjuvants, lymphokines.
1: vaccination (already know)
3. 2: Adjuvants
• An adjuvant, by definition, is a substance
when incorporated into or injected
simultaneously with antigen potentiates the
immune response.
4. Mode of action of adjuvant
• On antigen characteristics: Some adjuvants
affect the way in which antigen is presented.
The immune response is increased when
protein antigens are precipitated by alum.
• Other adjuvants prevent rapid dispersal of
antigen from the local tissues.
• The reservoir of antigen is available either at
an extra cellular location or within
macrophages.
5. Freund’s incomplete adjuvant
• where antigen, in the aqueous phase, is
emulsified with paraffin oil. Since paraffin oil can
produce severe local reactions.
• the use of liposomes , which are membrane
bound lipid vesicles, as agents for presentation of
antigen to the immune system.
• Liposomes are storage vacuoles for the antigen,
they also enter the macrophage and are
presented in a more immunogenic manner to T
cells.
6. • On host immune response: Most adjuvants,
however, do not affect the antigenic
characteristics but act on the host immune
response.
• Virtually all adjuvants stimulate macrophages, a
good example is Freund’s complete adjuvant
which is made from incomplete Freund’s adjuvant
with the addition of killed mycobacterium or
more recently, water soluble muramyldipeptide.
• Such adjuvants act directly on the macrophage or
via the T cell.
• Besides improving antigen presentation, they
enhance the accessory signals required for
lymphocyte activation and proliferation.
7. Types of Adjuvants
• Organic adjuvants: Organic adjuvants include a
variety of organic molecules obtained from
bacteria. Muramyldipeptide (MDP) is a
bacterial peptidoglycan. MDP increases both
humoral and cellular immunity.
8. • Synthetic adjuvants: Synthetic adjuvants that
increase host immunity include levamisole and
Isoprinosine.
• Levamisole was initially introduced as an
antihelminthic agent. It potentiates humoral and
cellular immunity in a fashion that is T cell
dependant. It has been used in the treatment of
cancer and rheumatoid arthritis.
• side effect is agranulocytosis.
• Isoprinosine is a complex containing inosine, a
purine precursor. It promotes T cell mitogenesis.
9. • Tuftsin : Tuftsin is a unique adjuvant that
occurs naturally and has been synthesized as
well.
• It is a four amino acid peptide( threonine,
lysine, proline, arginine ), homologous to a
sequence in the constant region of the
immunoglobulin heavy chain.
• Tuftsin primarily stimulates macrophages.
Since it occurs naturally it probably has a
physiologic role in host defense.
10. 3: Lymphokines
• It includes interferons & interleukins like IL-1,
IL-2 and IFN γ, IFN β, and IFN α.
• IFN α was the first to be produced in a large
scale manner. IFN α has proven adjuvant
properties, as assessed by reduction in tumor
size, especially in lymphomas. IFN α appears
to act both directly on tumor tissue and by
activation of macrophages.
• IFNs α, β and γ are all used therapeutically.
11. • Recombinant IL-2 was approved in 1992 for
the treatment of metastatic and inoperable
renal cell carcinoma.
• It has been used experimentally for malignant
melanoma and HIV infection.
• It appears to restore both humoral and
cellular immunity in nude mice. IL-2 also
appears to induce production of IFN α by T
cells.
• Side effects: fever, malaise, myalgia, arthralgia
and fluid retention.
12. Immunosuppression
• Immunosuppression has been particularly
useful is patients undergoing organ
transplants and in the treatment of graft
rejection, autoimmunity and allergy. Current
treatment of graft rejection, autoimmunity or
allergy is not antigen specific.
• It is divided into 2 categories: general
immunosuppression therapy & specific.
13. General immunosuppression therapy
1.Cytotoxic agents
• Cytotoxic agents such as cyclophosphamide,
chlorambucil, azathioprine and methotrexate
block cell replication and preferentially kill
dividing cells.
• Cyclophosphamide and chlorambucil alkylate
DNA in both dividing and resting cells, leading to
cell death during the mitotic phase of cell
division.
• Azathioprine and methotrexate block DNA
synthesis, killing cells that are in the S (DNA-
synthesis) phase of the cell cycle.
14. • Cytotoxic agents, however, also suppress both
humoral and cellular immunity.
• Because B cells or T cells that are stimulated by
antigen, go through active proliferation by
cytotoxic agents. This may not be the only way
that these drugs cause immunosuppression, as
they are an important part of the
immunosuppressive therapy given during
organ transplantation.
15. 2.Glucocorticoids
• Glucocorticoids are potent immunosuppressive
and anti inflammatory agents.
• They are used regularly in the treatment of graft
rejection, allergies and asthma.
• The immunosuppressive effects of glucocorticoids
is to reduce the levels of circulating lymphocytes
and monocytes and suppress the production of
IL-1 and IL-2.
• Glucocorticoids have a diversity of actions and
the clinical benefit seen in allergy and
autoimmunity.
16. 3.Fungal metabolites
• 1.Cyclosporine acts selectively on antigen-
sensitive T cells in the G0 to G1 and blocks the
transcription of lymphokine mRNA, &
suppressing IL-2 production.
• This effectively blocks T cell activation and
proliferation.
• Cyclosporine has been used successfully to
prevent graft rejection and in the treatment of
graft versus host disease.
• Side effects: toxicity for dividing cells in the gut
and bone marrow, nephrotoxic & hepatotoxic.
17. • 2. Tacrolimus is a macrolide that is an
immunosuppressant produced by the fungus
in a mechanism similar to that of cyclosporine
to prevent allograft rejection.
• 3. Rapamycin is structurally similar to
tacrolimus and it blocks the proliferation and
differentiation of activated TH cells in the G1
phase of the cell cycle.
18. • tacrolimus and rapamycin are 10–100 times more
potent as immune suppressants than cyclosporin ,
and can be administered at lower doses and with
fewer side effects than cyclosporin.
• cyclosporin has been shown to prolong graft
survival in kidney, liver, heart and heart-lung
transplants.
• In one study of 209 kidney transplants from
cadaver donors, the 1-year survival rate was 64%
among recipients receiving other
immunosuppressive treatments and 80% among
those receiving cyclosporin.
19. 4.Total Lymphoid Irradiation Eliminates
Lymphocytes
• Because lymphocytes are extremely sensitive
to x-rays , x-irradiation can be used to
eliminate them in the transplant recipient just
before grafting.
• In total lymphoid x-irradiation, the recipient
receives multiple x-ray exposures to the
thymus , spleen, and lymph nodes before the
transplant surgery.
20. • Because the bone marrow is not x-irradiated,
lymphoid stem cells proliferate and renew the
population of re-circulating lymphocytes.
• These newly formed lymphocytes appear to
be more tolerant to the antigens of the graft.
Specific immunosuppression therapy
21. 1. Monoclonal Antibodies Can Suppress
Graft-Rejection Responses
• Monoclonal antibodies to the T cell surface
antigen, CD3 and the IL-2 receptor have been
used for treating host rejection of allografts.
Both agents have been associated with several
problems.
• Monoclonal antibodies directed against various
surface molecules on cells of the immune system
have been used successfully to suppress T-cell
activity in general or to suppress the activity of
subpopulations of T cells.
22. • A strategy to deplete immune cells involves
use of a monoclonal antibody to the CD3
molecule of the TCR complex.
• Injection of such monoclonal antibodies
results in a rapid depletion of mature T cells
from the circulation.
• Another depletion strategy used to increase
graft survival uses monoclonal antibodies
specific for the high-affinity IL-2 receptor.
23. • Monoclonal-antibody therapy, which was
initially employed to deplete T cells in graft
recipients, also has been used to treat donors’
bone marrow before it is transplanted.
• Other targets for monoclonal-antibody therapy
are the cell-surface adhesion molecules.
Simultaneous treatment with monoclonal
antibodies to the adhesion molecules ICAM-1
and LFA-1 for 6 days after transplantation has
permitted indefinite survival of cardiac grafts
between allogenic mice.
24. 2.Blocking Co-Stimulatory Signals
Can Induce Anergy
• TH-cell activation requires a co-stimulatory
signal in addition to the signal mediated by
the T-cell receptor.
• The interaction between the B7 molecule on
the membrane of antigen-presenting cells and
the CD28 or CTLA-4 molecule on T cells
provides one such signal.
• Lacking a co-stimulatory signal, antigen
activated T cells become anergic.
25. • CD28 is expressed on both resting and
activated T cells and binds B7 with a moderate
affinity; CTLA-4 is expressed at much lower
levels and only on activated T cells but binds
B7 with a 20-fold higher affinity.
• A second pair of co-stimulatory molecules
required for T-cell activation are CD40, which
is present on the APC, and CD40 ligand (CD40L
or CD154), which is present on the T cell.
