Transplantation - 17, pages 260-270 Immunology – Lecture 4 The Well Patient: How innate and adaptive immune responses maintain - Health -13, pages 169-181, 191-195. Immune Deficiency - 15 Autoimmunity - 16 Transplantation - 17, pages 260-270 Tumor Immunity - 19

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

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, 479-491 (July 2012)

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

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

Immune Deficiency - 15

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

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

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

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.

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

Immune Def. – Monocytic defects Tuberculoid granuloma http://www.humpath.com/spip.php?article1080 CGD patient with Testicular abscess http://www.actasdermo.org/en/disseminated-sporotrichosis-with-cutaneous-and/articulo/90277513/?pubmed=true

Autoimmunity - 16

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)

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

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

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)

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

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

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

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

Type 1 diabetes – cell-mediated autoimmune disease Normal pancreatic islet Nature Reviews Immunology 10, 145-152 (February 2010) Insulin-independent diabetes Mellitus – infiltration of lymphocytes into the islet

Transplantation - 17

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)

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

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

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 10-20 years

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

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

Tumor Immunology - 19

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

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

Immune Surveillance

NK Recognition of Tumor Cell Targets

Cytokines with anti-tumor activity

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

Decreased expression of tumor cell MHC class I

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

Cancer Immunotherapies

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 http://www.cancer.gov/cancertopics/research-updates/2013/CAR-T-Cells

Herceptin Therapy https://beyondthedish.wordpress.com/2012/06/04/smart-bomb-successfully-treat-advanced-breast-cancer-in-clinical-trials/

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