1. Transplantation - 17, pages 260-270
Immunology – Lecture 4
The Well Patient: How innate and adaptive immune responses maintain - Health -13, pages ,
Immune Deficiency - 15
Autoimmunity - 16
Transplantation - 17, pages
Tumor Immunity - 19

2. Clinical Relevance of the Immune System
Immunology - Lecture 4
Clinical Relevance of the Immune System
The Well Patient: How Innate and Adaptive Immune Responses Maintain Health - 13

3. Immune responses to pathogens/pathogen-derived vaccines
Pathogens or vaccines derived from them contain PAMPS
Activate APC and other cells to produce cytokines that shape the immune system
APC will also present pathogen-derived peptides on MHCI to CD8+ and MHC II to CD4+ T cells
MHC-Pathogen Peptide Specific CD4+ T cells are directed by local cytokines to differentiate into appropriate immune response
B cells recognize soluble antigens, divide, and produce antibodies
Antibody generation are shaped by local cytokines
A subset of Ag-specific T and B cells
differentiate into memory cells that last decades
Desmet and Ishii. Nature Reviews Immunology 12, (July 2012)

4. Responses to Parasite are dominated by Th2 responses, IgE, and Granulocytes

5. Adaptive Immune Cell Memory Is the Reason for Successful Vaccinations
Immune memory:
1. Increases the number of
T and B cells that can potentially
recognize an antigen
2. Decreases
the intensity of the
stimuli need to activate
them
Memory increases intensity,
duration, and amplitude
of adaptive immune
response

6. Immune Deficiency - 15

7. Immune Deficiencies Primary: Caused by congenital or genetic defects
Over 100 identified - impacted gene is often known
Can often be treated now with BMT; attempts at gene therapy
Secondary: Environmental causes
Infection: HIV, Bacteria (TB, Strep), EBV
Therapeutic treatments: Chemotherapy, Immunosuppression, Irradiation
Cancer
Malnutrition

8. Immune Def. – Lymphoid defects
Examples:
Severe combine immune deficiency (SCID)
Loss of RAG1 and/or RAG2
Increased infections and related mortality

9. Immune Def. – T cell defects
Examples:
MHCII deficiency
“Bare lymphocyte syndrome”
CD3 Deficiency
Decreased cell mediated immune responses and humoral deficiencies

10. Immune Def. – B cell defects
Examples:
X-linked agammaglobulinemia from a failure in early differentiation of B cells
T cell functions OK
Increased overall susceptibility to infection
Treat with exogenous Ab
This is a rare disorder that mainly affects males. It is caused by a gene defect that blocks the growth of normal, mature immune cells called B lymphocytes.

11. Immune Def. – Monocytic defects
Examples:
Chronic granulomatous disease (CGD)
Myeloid cells can’t kill ingested microbes
Difficulty with Staph infections, fungi
Skin abscesses and pneumonia

12. Immune Def. – Monocytic defects
Tuberculoid granuloma
CGD patient with
Testicular abscess

13. Autoimmunity - 16

14. Self-tolerance
The ability of the immune system to effectively distinguish self from non-self and to refrain from attacking self Mostly results from the deliberate inactivation or destruction of lymphocytes bearing TCRs or BCRs that recognize and bind self-epitopes Innate cells are genetically wired to see non-self; ignore self Inactivation or destruction may occur during early development (central tolerance) or may be imposed on lymphocytes in the periphery (peripheral tolerance)

15. Central Tolerance
Occurs during the differentiation of B cells in the bone marrow and T cells in the thymus B cells and T cells that bind self-reactive epitopes during development are induced to undergo apoptosis Great majority of self-reactive cells eliminated before they enter the circulation

16. Peripheral Tolerance
Mechanisms that control or eliminate autoreactive B cells and T cells after they exit the bone marrow and thymus
Anergy
Suppression by Treg as well as other regulatory cells

17. Loss of Self-Tolerance
Molecular mimicry – Infections and autoimmunity (Example: Rheumatic fever)
Inflammation
Epitope spreading: Damage resulting from an infection releases self Ag that are recognized by autoreactive cells in the context of inflammation
Loss of suppression
Sequestered antigens - Damage to eye
Neoantigens: Self Ag modified by an extrinsic factor (chemical haptens)

18. Regulatory Cell Inhibition
Treg can prevent autoreactive responses by other lymphocytes, including autoreactive ones
Limitations:
Suppresses good immunity
Limited by local inflammation
TLR and local cytokines can block Treg functions to release autoimmune attack

19. Inflammation and Autoimmunity
In inflammatory sites local cytokines may be sufficient to drive effector responses of autoreactive T cells

20. Molecular
Mimicry
After a response to a microbe, effector molecules cross react with epitopes on host molecules
“Heterologous Immunity”

21. Molecular Mimicry Cardiac damage during rheumatic fever
Infection Group A Strep expressing M protein
Generates IgG that recognize Ag being presented in the heart similar to M protein

22. Type 1 diabetes – cell-mediated autoimmune disease
Normal pancreatic islet
Nature Reviews Immunology 10, (February 2010)
Insulin-independent diabetes
Mellitus – infiltration of
lymphocytes into the islet

23. Transplantation - 17

24. Transplantation (Tx)
In Tx the MHC is the genetic locus that dominates the determination of acceptance or rejection of tissue grafts
Defines the type of graft
Auto = Self MHC
Syn = Self MHC
Allo = Non-self MHC
Xeno = Non-human MHc
Xenograft are also limited by Non-MHC factors (Unique carbohydrates; critical regulatory proteins)

25. Histocompatibility differences among donor-recipient combinations results in rejection
Law of Tx: A recipient will mount an immune response against histocompatibility Ag (Major: MHC or HLA; Minor: peptides in MHC) not encoded in its own cells
Self to innate
Non-self to adaptive
H2b
H2d
H2k
H2dxb

26. Transplantation
Histocompatibility (HLA) differences among donor-recipient combinations results in rejection

27. Types of Tx rejection
Three main types of rejection defined by timing of rejection
Hyperacute–minutes
Avoid by pre-screening recipients for existing antbodies
Acute rejection – 6-12 months
Limited by T cell targeting
immunosuppression
Chronic rejection – Years
No effective cure
Results in a need for re-Tx after years

28. Bone marrow Tx (BMT) complications
BMT is a common treatment for cancer and genetic disorders Donor T cells can recognize HLA of recipient and cause a serious pathological state called Graft-vs.-host disease (GVHD) 50% of BMT patients suffer GVHD 10% of GVHD is resistant to immunosuppression, resulting in 90% mortality in this group

29. Therapeutic Intervention
Immunosuppression
Corticosteroids (anti-NF-kappaB activity)
Calcineurin Inhibitors (Block TCR)
Anti-proliferative agents (Block Co-stim or Cytokine)
Targeted immune cell depletion with antibodies
All lymphocytes; B cells; T cells
General immunosuppressive therapy
Lack specificity
Produce generalized immunosuppression
Increase recipient’s risk for infection
Does not block chronic rejection

30. Tumor Immunology - 19

31. Tumor Ag Tumor-specific: Ag unique to malignant cell
Mutation of genes (Ras mutants, P53)
Rare
Typically poorly immunogenic – need to produce peptides that bind well into MHC
Tumor-associated: not unique to tumor, but expressed in altered fashion
HER2/neu – overexpressed in 20-30% of breast cancer
MAGE-3 – oncofetal Ag expressed on fetal tissue and wide variety of tumors

32. Immune Surveillance
Innate – first line of immune defense against tumors. These nonspecific mechanisms prevent the spread of malignant disease.
NK Cells
Cytokines
Adaptive – specific antigen–dependent immune responses against antigens on tumor cells.
Antibodies
CTLs
However, there will be little non-self activation of APC – thus poor immune response generated and sustained

33. Immune Surveillance

34. NK Recognition of
Tumor Cell Targets

35. Cytokines with anti-tumor activity

36. Immune Evasion
Tumor cells often escape the immune system and go on to produce tumors and diseases that are often fatal. Several mechanisms facilitate evasion against immune response by tumor cells.
Modulation of tumor antigens
Modulation of MHC class I expression
Harnessing repair and suppression pathways, especially Treg and induction of anergy

37. Decreased expression of
tumor cell MHC class I

38. Cancer Immunotherapy
Cancer immunotherapy is based on enhancement of the natural immune responses that the body mounts against malignant cells
Cytokine therapy
Monoclonal antibodies and biologicals
Cancer vaccines
CTL immunotherapies
Evolved understanding of immune system has lead to recent breakthroughs

39. Cancer Immunotherapies

40. CAR T-Cell Therapy
Rx of leukemia and lymphoma with T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous
Side effects – B cell depletion
Cytokine-release syndrome

41. Herceptin Therapy

42. Anti-PD-1 Therapy
Sheridan. Nature Biotechnology 30, 729–730 (2012)