Essential-Clinical-Immunology-John-

B.-Zabriskie-MD-1-2009-Cambridge-
University-Press-9780511465291-
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Annas-Archive
Immune Regulation
Introduction to Immune Regulation
Immune system responds to foreign antigens.
Some diseases result from defective or over-responsive immune system.
Therapeutic approaches: immunosuppression or immunopotentiation.
Immunosuppression
Immunosuppressive Drugs
Corticosteroids: alter immune responses, used in graft rejection and autoimmune diseases.
Thiopurines: e.g., azathioprine, inhibits DNA synthesis in dividing cells.
Alkylating agents: e.g., cyclophosphamide, inhibits cell division and antibody production.

Immune Regulation
Immunosuppressive Methods
Antibodies
Anti-RHD antibodies used to prevent hemolytic disease of the newborn.
Monoclonal Antibodies Approved for Cancer Therapeutics
Various antibodies and drugs with their modes of action listed.
Examples include corticosteroids, azathioprine, methotrexate, cyclosporine, and tacrolimus.
Mechanisms involve inhibition of cytokine genes, nucleic acid synthesis, and T-cell activation.

Monoclonal antibodies are used to suppress the immune system

"Humanized" mouse monoclonals are created by transposing mouse antigen-binding sites onto a
human antibody framework
Used for treating autoimmune diseases by targeting cell surface molecules or soluble mediators
of inflammation
Effective in treating severe rheumatoid arthritis by targeting tumor necrosis factor (TNF-α)
Also used as antitumor agents by linking tumor antigen-specific monoclonal antibodies to
cytotoxic drugs, radioisotopes, or toxins
Approved uses of monoclonal antibodies include non-Hodgkin’s lymphoma, leukemia, breast cancer,
and colorectal cancer
 Ongoing clinical trials for prostate cancer treatment and potential future uses against various other
tissues

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Immunosuppression methods include plasmapheresis or plasma exchange
Total lymphoid irradiation for long-term suppression of helper T cells used in severe autoimmune
diseases
Immunopotentiation aims to potentiate the host immune response to control chronic infections like HIV
and hepatitis C
Three ways to potentiate the immune response in humans: through cytokines, adoptive immunotherapy,
or vaccination
Interferons are antiviral glycoproteins with antitumor and immunomodulatory effects, used as immuno-
therapeutic agents
Three groups of interferons: alpha (α), beta (β), and gamma

Table 3.2:
Lists immunosuppressive drugs in clinical use or clinical trials
Includes brand names, generic names, type of monoclonal antibody, target, and indication for drugs like
Rituxan, Herceptin, Mylotarg, etc.

Immune Regulation
Interferons
Three types: IFN-α, -β, and -γ.
IFN-α is best studied and used for hepatitis B and C.
Side effects of IFN-α include flu-like symptoms and reversible effects like bone marrow
depression.
IFN-β beneficial for multiple sclerosis patients.
IFN-γ used for conditions with defective macrophage function.
IL-2
Produced by CD4 T cells.
Used in immunodeficiency states like HIV.
Side effects similar to IFN-α, with severe effects on vascular permeability.
Adoptive Immunotherapy
Involves transferring cells or antibodies into a host.
Examples include hepatitis B immune globulin and adoptive transfer of antigen-specific T
lymphocytes.
Immunization
Prevention of infectious diseases through clean water, sanitation, nutrition, and hygiene.
Vaccination is crucial for controlling infectious diseases.

Immune Regulation
Active and Passive Immunity
Active immunity from exposure to a foreign stimulus.
Artificial active immunization through vaccines.
Types of Vaccines
 Live attenuated vaccines mimic natural infection.
Killed vaccines consist of killed organisms or their products.
Killed vaccines less effective than live vaccines, require boosters.
Adjuvants
Enhance immune response to killed organisms.
Aluminum compounds commonly used in humans.
Other adjuvants like muramyl dipeptide and Quil A are being developed.
Gardisal Vaccine
Protects against human papillomavirus (HPV) to prevent cervical cancer.
Targets high-risk viral serotypes to reduce cervical cancer risk.
Potential for preventing other diseases like Burkett’s lymphoma.

Cytokine Immunomodulation
Techniques focus on humoral arm of immune response
Targeting T cells and cytokine regulators for regulating immune responses
Cytokines regulate immune responses with high redundancy
IL-2 and IL-15 share common signaling pathways involving JAK1, JAK3, and STAT5
IL-2 prevents T-cell immune response to self, while IL-15 maintains memory response to
pathogens

Differences in IL-2 and IL-15 Functions

IL-2 involved in immune system checkpoints and AICD
IL-15 acts as an anti-apoptotic factor and maintains CD8+ CD44 memory T cells
IL-2 deficiency leads to autoimmune diseases, while IL-15 deficiency reduces certain immune cell
populations
Immunotherapy Targets
IL-2Rα system targeted for immunotherapy due to its expression in malignant cells and cells
involved in autoimmune diseases
Antibodies against IL-2Rα specifically destroy IL-2 dependent cells
Role of IL-15 in Autoimmune Diseases
IL-15 may contribute to autoimmune diseases by inducing TNF-α expression and inhibiting self-
tolerance
Dysregulated IL-15 expression reported in autoimmune diseases like multiple sclerosis and
psoriasis

This section discusses the role of cytokines like IL-2 and IL-15 in immune regulation, their functions, and
implications for autoimmune diseases and immunotherapy.

Immune Regulation
Targeting IL-15 for immune regulation
TNF-directed therapies not effective for all patients
IL-15 targeting aims to achieve anti-inflammatory effects and reduce self-reactive memory T cells
Agents inhibiting IL-15 activity developed: soluble IL-15Rα, mutant IL-15 molecules, antibodies
specific for IL-2/IL-15Rβ
Examples of effects in vivo: reduced hypersensitivity responses, increased survival of pancreatic
islet cell allografts, inhibited arthritis development, and allograft rejection
Clinical trials with IL-15 specific antibodies in mouse models of psoriasis and rheumatoid arthritis
Cellular Vaccines and Modulations
Dendritic Cell (DC) Vaccines in cancer treatment
Progress in cancer patient survivals with autologous DCs expressing specific proteins
Importance of the type of DC in vaccine potential
Monocyte-derived DCs as potent stimulators of immunity, easy to generate in large numbers
Maturation of DCs crucial for inducing strong immunity
Antigen delivery on immature DCs can induce tolerance
Monocyte-derived DCs used in treating melanoma patients with defined antigens or tumor lysates
Use of fetal calf serum during DC generation may contribute to observed effects
Comparison of immunogenicity between immature and mature DCs in clinical studies

Immune Regulation
Differentiation between immature and mature DCs:
Both types showed an expansion of peptide-specific T cells.
Only mature DCs induced IFN-γ-producing and lytic CD8+ T cells.
Immature DCs might induce regulatory T cells instead of effector T cells.
Breaking immunological tolerance:
Idea of breaking tolerance to self-antigens to target cancers more than normal tissues.
Chemotherapies have shown clinical benefit in this aspect.
Approaches in creating cancer vaccines:
Using allogeneic cell lines, differentiation antigens, cancer testes antigens, and common
molecules.
Subthemes include targeting CT antigens over differentiation antigens and using mutated
antigens for breaking tolerance.

Importance of Innate Immunity

Inclusion of immune modifiers in cancer vaccines:
QS21, ISCOMS, Montanide, heat shock proteins, CpG, BCG, GM-CSF are essential components.
Anecdotal success of Coley’s toxin in the past may be reinterpreted with new immune response
modifiers.
Delivery agents for antigens:
Options include whole proteins, peptides, RNA, DNA, viral vectors, DCs, etc.

Controls on T Cells and Enhancing Antitumor

Activity
Enhancing antitumor T-cell activity:
Use of blocking antibodies to inhibitory T-lymphocyte antigen CTLA-4, manipulation of regulatory
T cells, antibodies to PDL or PDLI, and enhancement of co-stimulating molecules like B7 on
antigen-presenting cells.