CHAPTER

1212Immune Responseto Biomaterials

12-1 Introduction: Overview of Acquired Immunity Innate immunity vs. Acquired immunity

Immunotoxicity: adverse effects on immune system and other body systems Acquired immunity

specificity / diversity / self & non-self recognition / immunologic memoryhumoral immunity (B-cell) and cellular immunity (T-cell)

Biomaterials roles hapten and adjuvant

12-2 Antigen Presentation and Lymphocyte Maturation 12.2.1 Major Histocompatibility Complex (MHC) Molecules

Antigen presentation with either MHC-I and MHC-II

(1) MHC-Class I all nucleated cells Tc

(2) MHC-Class II antigen-presenting cells (macrophages, B-cells, dendritic cells)

(3) MHC molecular variation 3 genes for each MHC-I and II tissue rejectiontissue typing

(4) Intracellular Complexation with MHC-Molecules a. endogeneous antigens --- proteolysis --- peptides --- MHC-1 in ER

--- cell surface exposure b. exogeneous antigens --- phagocytosis --- proteolysis in endosome

--- MHC-II binding in the endocytotic vesicles

12.2.2 Maturation of Lymphocytes

10,000 Ab/TcR (single specificity) – gene rearrangement – immunologic diversity

12.2.3 Activation and Formation of Clonal Population

12-3 B-cells and Antibodies 12.3.1 Types of B-cells

plasma cellsmemory cells

12.3.2 Characteristics of B-cells(1) Structure of antibodies

(2) Classes of antibody (3) Mechanism of Ab action agglutination precipitation neutralization lysis

phagocytosis (effector function) complement activation

12-4 T Cells 12.4.1 Types of T-cells TH-cell and TC-cell

12.4.2 Helper T cells cytokines from TH-effector cells

(1) B-cell growth and differentiation (IL-4, 5, 6)(2) TC-cell proliferation (IL-2) (3) TH-cell activation (IL-2) (4) Promotion of chemotaxis and activation of macrophages (MIP & IL-8)

12.4.3 Cytotoxic T cells cytotoxic T-lymphocytes (CTL) --- perforins --- cell lysis --- disengagement

--- another ‘altered self’ cells (virus infected or cancer cells)

12-5 The Complement System innate immunity ~ 20 plasma proteins --- action cascade --- elimination of foreign elements

via memb-attacking complex formation

12.5.1 Classical pathway / 12.5.2 Alternative pathway / 12.5.3 Memb attack complex

12.5.4 Regulation of the Complement System localized action and preventing host cell lysis (1) Short half-life of certain enzymes

C3b degradation by C3 convertase away of target by 40 nm (2) C3b and MAC regulation

C5b67 --- no membrane insertion --- leak and attack bystander cells amplification sites

(3) Regulatory proteins competing for key binding sites

RCA proteins (regulator of complement activation) a. C4b + RCA (no C3 convertase) b. C3b + RCA (no C3 convertase) c. C8 + RCA (no poly-C9 complex) d. DAF (decay-accelerating factor) --- C3 convertase binding

12.5.5 Effects of the Complement System (1)Complement system amplifies the actions of Ab. (2)Complement system stimulates the inflammatory response.

mast cell and basophil binding chemotaxis of monocytes and neutrophils / macrophage adhesion

(3) Phagocytosis C3b --- foreign surface --- macrophage and neutrophils

uptake of the opsonized particle

12-6 Undesired Immune Responses to Biomaterials 12.6.1 Innate vs. Acquired Responses to Biomaterials no rejection / no destruction / immunocompatibility complement activation --- accumulation of inflammatory cells --- device failure

12.6.2 Hypersensitivity or Allergic reaction unusual, excessive or uncontrolled immune reaction (1) Type I: IgE mediated

allergen --- IgE plasma cell --- receptors of basophils and mast cells --- Ab X-linking --- degranulation of mast cells --- histamine release --- vasodilationand smooth muscle contraction

(2) Type II: Antibody mediated antibody and complement to destroy cells or platelets with foreign antigen

on the surface (3) Type III: Immune complex mediated Ag + Ab complex --- ppt --- complement activation and phagocytic cell migration --- enzyme and active substance release --- tissue damage (4) Type IV: T-cell mediated (= delayed-type hypersensitivity) allergen on APC --- TDTH cell --- cytokines --- macrophage attraction --- lytic agent release --- local tissue damage (5) Hypersensitivity and the classes of biomaterials a. metals b. ceramics c. polymers d. protein coats

non-self

12-7 Techniques: Assays for Immune Response materials --- lymphocytes and inflammatory cells --- stimulation

12.7.1 In vitro assays (1) cell adhesion and spreading (2) cell death (3) cell migration (4) cytokine release (5) cell surface marker expression (6) cell proliferation

expansion of clonal populations LTT (lymphocyte transformation tests) migration (small scale) ELISA FACS

12.7.2 In vivo assays (1) histology/immunohistochemistry (lymphocytes) (2) immune response (blood from the animal) (3) Ag from the biomaterials

skin test for localized inflammation