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`& Practice
`
`I
`
`SIXTH EDITION
`
`@dition
`
`' '
`N. FRANKLIN ADKINSON, JR. • JOHN W. YUNGING.ER
`WILLIAM W. BUSSE • BRUCE S. BOCHNER
`
`STEPHEN T. HOLGATE • F. ESTELLE R. SIMONS
`
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1022 - Page 1
`
`

`

`M
`
`I D D L E T 0 N
`
`s
`
`ALLERGY
`
`·l r I
`
`Principles & Practice
`
`VOLUME
`
`EDITED BY
`
`N. FRANKLIN ADKINSON, Jr., MD
`Professor of Medicine and Training Program Director
`Division of Allergy and Clinical Immunology
`The Johns Hopkins Asthma and Allergy Center
`The Hopkins Bayview Medical Campus
`Balti more, Maryland
`
`BRUCES. BOCHNER, MD
`Professor of Medicine and Director
`Division of A llergy and Clinical Immunology
`The Johns Hopkins Asthma and A llergy Center
`The Hopkins Bayview Medical C ampus
`Baltimore. Maryland
`
`l
`
`JOHN W. YUNGINGER, MD
`Emeritus Consultant in Pediatrics and Internal Medicine
`(Allergy)
`Mayo Clinic and Foundation
`Emeritus Professor of Pediatrics
`Mayo Medical School
`Rochester, Minnesota
`
`WILLIAM W. BUSSE, MD
`Charles E. Reed Professor of Medicine
`University of Wisconsin Hospital and Clinics
`Head, Allergy and Clinical Immunology
`Department of Medicine
`University of Wisconsin School of Medicine
`Madison, Wisconsin
`
`STEPHEN T. HOLGATE, MD, DSc, FRCP, FMed Sci
`MRC Clinical Professor of Immunopharmacology
`Southampton General Hospital School of Med icine
`University of Southampton
`Southampton, United Kingdom
`
`F. ESTELLE R. SIMONS, MD, FRCPC
`Professor and Head
`Section of Allergy and C lin ical Immunology
`Department of Pediatrics and Child Health
`University of Manitoba
`Winnipeg. Manitoba, Canada
`
`SIXTH EDITION
`
`With more than 683 illustrations and 35 color plates
`
`A n Afliliate o f Elsev ier
`
`-
`
`- - - - - - - - - · ·
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1022 - Page 2
`
`

`

`An Affiliate of Elsevier
`
`The Curtis Center
`Independence Square West
`Philadelphia, Pennsylvania 19106
`
`MIDDLETON'S ALLERGY PRINCIPLES & PRACTICE. 6TH EDITION
`Copyright © 2003, Mosby, Inc, All rights reserved,
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1022 - Page 3
`
`

`

`SECTION A
`IMMUNOLOGY
`
`CHAPTER J
`The Immune System
`An Overview
`(cid:127) William T. Shearer and Thomas A. Fleisher
`
`The practice of allergy at the level of pathogenesis and ther(cid:173)
`apy has its roots in the science called immunology, the field
`that codifies the components and describes the functions of a
`human host defense system designed to protect against chem(cid:173)
`ical su bstances, microorganis ms, and cancer. This host
`defense system comprises specific cellular and numerous pro(cid:173)
`tein components that interact in a highly complex manner and
`that, in essence, act to preserve self and to neutralize or
`destroy nonself Over the process of evolution, this system has
`developed into a remarkably effic ient mechanism for protect(cid:173)
`ing human life. However, as part of, or as a consequence of,
`this preservation system, immune responses have evolved that
`prove inadequate or detrimental , leading to human disease.
`Allergy is a clear example of the detrimental side of the
`immunologic system, an overreaction in certain individuals
`by a specific defense pathway that responds inappropriately to
`environmental encounters and results in annoying and some(cid:173)
`times debilitating secondary effects. A llergy is the study and
`treatment of human hypersensitivity reactions directed at non(cid:173)
`se lf molecules termed allergens; this contrasts with these
`same hypersensitivity mechanisms providing protection when
`responding to parasitic infection. Thus. allergy is an integral
`part of the manifestation of immunity. and physicians who
`treat allergic disease must understand the scope and breadth
`of the science of immunology. The notion that allergists
`practice in a vacuum of sc ientific design and treatment is
`incorrect. Rather, the allergist, armed with the knowledge of
`underlying immunopathogenetic principles of allergic disease
`and the capability of exploiti ng the immunologic basis of
`allergy, will be able to relieve patient symptoms with scientif(cid:173)
`ically based therapeutic measures.
`This chapter summarizes current knowledge of the origins
`of the immune system, the interworkings among the constituent
`pa1ts of the immune network, and the varied consequences,
`including allergy, of the host immune response. This chapter
`serves as a reference point for all subsequent chapters, which
`di scuss the clinical presentations, treatments, and manage(cid:173)
`ment strategies of allergic disease.
`
`FEATURES OF TIIE IMMUNE SYSTEM
`Over the past 200 years, and particularly the last 25 years, the
`resistance mechanisms against communicable diseases have
`been documented and explained, even visualized. The basic
`
`property of the immune system is that it can distingui sh nonse(f'
`from self, a power that promotes survival and exists in a delicate
`balance between tolerance to self and response/rejection of
`non self. Autoimmuni(v defines a state in which tolerance to self
`is lost. This implies that responses against self do not normally
`occur and that if they do occur with sufficient magnitude and
`duration, the outcome is harmful to the host. However, not all
`responses to self are harmful, but rather the capacity to recog(cid:173)
`nize self in the context of specific cell surface molecules
`encoded by the major hisrocompatibility complex (MHC) and
`in antiidiotypic responses is important for the control and nor(cid:173)
`mal functioning of the intact immune system. Implicit in the
`recognition of nonself is the resultant capability for the rejec(cid:173)
`tion of nonself by the immune system. Although this power of
`the immune system to recognize and rej ect nonself can under
`unusual circumstances initiate self-destructive autoimmunity,
`by and large the immune system has preserved vertebrate
`species from the microbial and parasitic forces that seem
`programmed to destroy them. The extraordinary measures that
`are necessary to circumvent the forces of immune rejection,
`as required in transplantation and autoimmunity medicine,
`illustrate the complex strengths of these p1imal survival mech(cid:173)
`anisms. These measures involve powerful immunosuppressive
`drugs, irradiation, and antilymphocyte antibodies that are nec(cid:173)
`essary to restrain the more serious rejection episodes, leaving
`the patient immunologically suppressed, particularly vulnera(cid:173)
`ble to opportunistic infection, and other complications.
`
`Immune Memory
`A remarkable aspect of the immune system is its property of
`memory, which provides protection against harmful microbial
`agents despite reexposure being separated by prolonged peri(cid:173)
`ods, even decades. Immunolog ic memory is made possible by
`the clonal expansion of lymphocytes in response to antigen
`stimulation. From the time the human immune system first
`begins to differentiate in fetal life, uniquely reacting lympho(cid:173)
`cytes are created by the random recombination of segments of
`deoxyribonucleic acid (DNA) that code for antigen receptors
`expressed on the lymphocyte cell membrane. Through the
`expression of these receptors, each of the lymphocytes has the
`abil ity to bind to and become activated by a specific non-self
`antigen, either natural or artificial. lnteraction with antigen
`not only activates the lymphocytes, but also results in the
`
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`2
`
`SECT/ONA
`
`Immunology
`
`generation of long-lived antigen-specific memory cell clones.
`Thus in the future, when the same antigen enters the body,
`there is an immediate recognition by these memory cells. Both
`cellular and humoral responses to the antigen a.re produced
`quickly, which offers protection in the case of an infectious
`agent or neoplastic cell, and another round (boosting) of mem(cid:173)
`ory cell generation ensues. This process of expansion of clonal
`populations of uniquely reacting lymphocytes first explained
`the B lymphocyte origin of antibody diversity and applies to
`cellular (T lymphocytes) immune responses as well. 1.2
`
`Surveillance
`Because of the early documentation of immune memory, a
`theory of immune surveillance arose that purported that the
`immune system was in a perpetual state of vigilance, screen(cid:173)
`ing and rejecting any nonself entity that appeared in the body.
`According to this theory, bacteria, viruses, and cancer cells
`are being regularly countered by this surveillance mechan ism.
`However, criticism of this theory originates from the observa(cid:173)
`tion that, despite protection offered by the system, fatal malig(cid:173)
`nancies frequently arise.3.4 Nevertheless, the phe nomenal
`explosion of the acquired immunodefici e ncy synd rome
`(AIDS) epidemic has demonstrated that the immune system,
`particularly the CD4+ T lymphocyte, plays a cruci al role in
`preventing the acquisition of fatal opportunistic infections and
`the early appearance of at least certain malignancies, includ(cid:173)
`ing Kaposi's sarcoma and lymphoid cancers.5
`
`Tolerance (Central vs. Peripheral)
`Tolerance is the process by which the immune system is pro(cid:173)
`grammed to eliminate foreign substances such as microbes,
`7
`toxins, and neoplastic tissues but to accept self-antigens.6
`·
`This process depends on the express ion of unique B and T cell
`antigen receptors, involving somatic gene recombination
`events during cell development. Lymphocyte receptor genes
`recombine to give antigen specificity. When the lymphocyte
`that expresses rearranged receptor genes is stimulated by
`binding of the appropriate specific antigen to the receptor, the
`cell propagates, signaling the initial step toward elimination
`of the antigen or the cells bearing the foreign anti gen.
`Immunologic self-tolerance is not complete at bi rth but is
`actively acquired and maintained during life. Several mecha(cid:173)
`nisms may be operating. One mechanism is central clonal
`deletion, resulting in the elimination of self-reactive immature
`T lymphocytes in the thymus and self-reactive B lymphocytes
`in bone marrow. The process of central tolerance occurs in
`lymphoid tissue and is not complete because not all self(cid:173)
`antigens are expressed in these organs. Peripheral LOlerance
`appears to be maintained by several mechanisms, including
`clonal deletion, anergy, suppression, and clonal ignorance.
`Clonal anergy results in T cells incapable of responding to the
`specific antigen, whereas deletion results in the elimin ation of
`a utoreactive T lymphocytes. Other nonlymphoid cells may
`induce suppression of self-antigen- reactive T cells, whereas
`naive T cells may ignore some self-antigens.
`
`Biologic Amplification System
`Although the memory capabilities of the immune system are
`conveyed by lymphocytes, a combination of cellular and
`
`humoral components of the immun e and inflam matory sys(cid:173)
`tems are necessary for appropriate host defense. This combi(cid:173)
`nation of elements in the immune response is considered part
`of a biologic amplification srstem that greatly augments the
`capability of the immune response. Thus, both soluble mol e(cid:173)
`cules (e.g., activated comple ment proteins. interleukins,
`chemokines, other cytokines) and cellular components (e.g.,
`poly morphonuclear leukocytes, monocytes, macrophages,
`eosin ophils, basophils, mast cell s; the "inn ate" immune
`response) greatly amplify the recognition and rejection power
`of lymphocytes.8 9 Viewed from this perspective, many
`portions of the inflammatory a nd immune response beco me
`integrated into an e legant and multifaceted system that
`distinguishes self from no nself.
`Perhaps the clearest examp le of the cells and mediators of
`the allergic response participating in host defense is the pro(cid:173)
`tective role that eosinophi!s and im111u11oglobuli11 E (lgE) play
`in parasitic infection. 10 Eosinophils facilitate destruction of
`larvae by the release of cytotox ic proteins (e.g .. major basic
`protein) when the eosinophil Fe receptor (FcR) FcaR (CD89)
`or FcyRII (CD32) binds immunoglobulin A (IgA) , lgG, or IgE
`specifically bound to the he lminths. All these antiparasiti c
`responses involving mast cells, eosinophils, and immuno(cid:173)
`globulin are exquisitely dependent on T cell control. Here, too,
`other components of the immune system, such as macrophages,
`neutrophils, and complement components, amplify the cyto(cid:173)
`toxic effects of the immediate hypersens itivity system. The
`combined power of these various components of host defen se
`enables individuals to survive the myriad of insults from bio(cid:173)
`logic and c hemical agents.
`
`CONSTITUENTS AND DEVELOPMENT OF THE
`IMMUNE SYSTEM
`All the cells of the immune syste m derive from the bone mar(cid:173)
`row ; in fact, all the inflam matory and ancillary cells that work
`in concert with the primary cells of the immune system derive
`from the pluripotent stem cell (Figure 1-1 ). This pluripoten(cid:173)
`tial stem cell gives ri se to a lymphoid stem cell and a myeloid
`stem cell. The lymphoid stem cell differentiates in to three
`types of cells-
`the T lymphocyte, the B lymphocyte. and
`the 110 11-T. non-B natural killer (NK) cell progenitor- and
`contributes to the development of subsets of dendritic cells.
`The myeloid stem cell gives rise to dendritic cell s, mast
`cells, basophils. neutrophil s. eosinophils, monocytes. and
`macrophages, as well as megakaryocytes and erythrocytes.
`Differentiation of both these committed stem cells is critically
`dependent on an ,may of cytokine and cell-ce ll interactions.
`An ever-increasing number of biologically important surface
`membrane proteins are being characterized on cells of the
`immune system. Many of these molecules have been assig ned
`a sequential number based on the cluster of differentiation
`(CD ) nomenclature.
`
`T Cell Development: Role of Thymus
`Lymphoid stem cells leave the bone marrow through the
`bloodstream. Some cells enter the thymus gland and, by a
`poorly understood process, remain in the thymus gland, where
`precursor cells ultimately develop into mature T cell s, emerg(cid:173)
`ing with distinct genome, surface antigen, and functional
`12 When the lymphoid stem cell
`characteristics (Fig ure 1-2). 1 1
`·
`
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`
`

`

`Pleuripotent
`hematopoietic
`stem cell
`
`Lymphoid
`stem cell
`
`Thymus DJ
`l
`
`Dendritic cells
`Monocytes
`Neutrophils
`Eosinophils
`Mast cells
`Basophils
`Platelets
`Erythrocytes
`
`Tcell
`NK cell
`Plasma cell
`FIGURE 1-1 Derivation of the cel ls of the immune system and he matopoi(cid:173)
`etic system. Pluripotent stem cells are deri ved from the yolk sac and
`ultimately reside in the bone marrow. All lymphocytes are deri ved from the
`lymphoid ste m cell and differentiate into three types of lymphocytes: ( 1)
`mature T cells after passage through the thymus gland. (2) large granular
`lymphocyte cells that possess natural ki ller (N K) function. a nd (3) B cells
`that can differentiate into plasma cells capable or secreting antibodies.
`Monocytes and macrophages are deri ved from mye loid stem cells: in
`addition, neutrophi ls, eosinophils. e rythrocytes, megakaryocytes. mast
`cells, basophils, and dendritic cells are also derived from this stem cell. The
`differentiation of stem cells into mature specialized cells is under the control
`of numerous cytokines and cel l-secreted factors.
`
`CHAPTER 1
`
`The Immune System
`
`3
`
`Bone marrow
`
`t
`
`Blood stream
`
`t Thymus © t
`
`CD4- , CDs(cid:173)
`TC Ra-, 13-
`
`CD4+, CDB(cid:173)
`TCRa+, 13 '
`
`Bloodstream
`
`t
`
`Lymph tissue
`
`FIGURE 1-2 Ontogeny a nd lineage relationships of matu ring T cells
`expressing TCRo.~. Most thymocytes express both CD-l and CD8. T cell
`antigen receptor (TCR) expression commences in this double-positi\'e stage.
`beginning with low numbers of receptors on each cell and increasing as mat(cid:173)
`urati on proceeds. Single-positi ve. that is, CD4+ or CDS· TCR-a~-express(cid:173)
`ing. mature cells are selected from this population. A small population of
`double-negative T cells bearing TCR-y8 a lso leave the thymus (not shown).
`
`enters the thymus, it lacks surface antigens, including the T
`cell antigen receptor (TCR) complex and mature T cell mark(cid:173)
`ers (e.g., CO4, CDS) that are associated with specific effector
`functions. These "double-negative" thymocytes (CO4-/COS-)
`are induced to express COl , CO2, CDS, CO6, CO7, and
`interleukin-2 receptor (1L-2R) molecules, which subserve
`critical receptor-ligand functions during early ontogeny.
`Subsequently, these progenitor T cells undergo development
`into descendant cells with rearranged alpha (a) and beta (~)
`( or gamma and delta) genes of the TCR, resulting in immature
`T cel1s. Cell surface expression of the TCR depends on
`coexpression of the CD3 molecule, which is a cluster of
`gamma (y), delta (o), epsilon (£), and zeta (/;) chains (see
`below). 13 Together, the TCR and CO3 molecules form the
`TCR complex.
`As the cells progress through ontogeny within the thymus,
`positive and negative selection occurs. resulting in release of
`mature T cells that have the capacity to distinguish between
`self and nonself antigens presented in the context of self(cid:173)
`MHC molecules. This maturation process is under the control
`of specialized cortical cells of the thymus, either by cell-to(cid:173)
`cell contact or by elaboration of cytokines, and it results in the
`elimination of most precursors that enter the thymus. For the
`
`most part, two cell types leave the thymus and begin to circu(cid:173)
`late in the peripheral blood, lymphatic system, and tissues:
`TCR-a~+/CO4+ T cells and TCR-aW/CDS+ T cells. Less than
`10% of mature T cells emerge from the thymus as TCR-yo+ T
`cells, which are predominantly co4-1cos-, and whose phys(cid:173)
`iologic role is j ust emerging. All peripheral T cells bear the
`TCR complex, and thus CO3 represents a pan-T cel l marker.
`T cell activation occurs when the TCR binds to immunogenic
`epitopes displayed on a cell (see below). CDS+ T cells recog(cid:173)
`nize antigenic peptides displayed in the context of class I
`MHC molecules, which are displayed on virtually all nucle(cid:173)
`ated cells, whereas CD4+ T cells recognize antigens presented
`in the context of class 11 MHC molecules, which are found on
`a limited range of cells referred to as antigen-presenting cells
`(APCs: monocytes, macrophages, B cells, dendritic cells).
`Altho ugh CO4+ T cells are sometimes fun ctionall y
`referred to as helper T cells and cos+ T cells as cytotoxic T
`cells, CD4+ T cells and COS+ T cells can have diverse fu nc(cid:173)
`tions. Thus, these phenotypes should be recognized for their
`capacity to respond to antigen in the context of MHC. The
`CD3 complex of proteins transduces the effect of antigen
`recognition by producing a signal through the cell membrane
`lipid bilayer to the cell interior and nucleus (see below).
`
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`

`4
`
`SECT/ONA
`
`/111111,mology
`
`Table 1-1 Accessory Molecules (Receptor-Ligand
`Pairs) that Stabilize the Binding of T Lymphocytes
`to Antigen-Presenting Cells (APCs)
`
`T Cell
`
`APC
`
`T cell receptor
`CD4
`CDS
`CDI la (LFA-la), CDIS
`(LFA- 1~)
`CO2 (LFA-2)
`CD40L
`CD28
`
`HLA and peptide
`HLA-DR, HLA-DQ, HLA-DP
`HLA-A, HLA-B, HLA-C
`CD54 (!CAM- I), ICAM-2, ICAM-3
`
`CD58 (LFA-3)
`CD40
`CDSO (B7)
`
`LFA, Leukocyte function-associated antigen: !CAM, intercellular adhesion
`molecule.
`
`Essential to the proliferation of antigen-activated T cells is
`their expression of the CD25 (IL-2R o:. chain, p55) which
`combines with the p chain (p75, CD 122) and)' chain (CD 132)
`to form the high-affinity JL-2R. Signaling through this recep(cid:173)
`tor initiates the production of IL-2, resulting in autocrine cell
`growth. A number of accessory glycoprotein adhesion mole(cid:173)
`cules stabilize the binding of T cells to the APC during the
`recognition phase or to the target cell in the effector phase,
`as well as providing for a co-stimulatory signal required for
`T cell activation (Table 1-1 ).
`
`Major Histocompatibility Complex and
`Immune Response
`The biologic basis for antigen recognition in the context of
`MHC molecules is to allow distinction between self and
`nonself. In humans the MHC gene complex is located on
`chromosome 6 and compri ses genes that code for human
`leukocyte antigen (HLA). 1
`~ Class I MHC molec ules (HLA-A,
`HLA-B, HLA-C) are composed of a 44-kD variant chain that
`is noncovalently associated with the 12-kD non-MHC
`invariant chain, P?-microglobulin. Class II MHC molecules
`(HLA-DR, HLA-DQ, HLA-DP) are composed of a 34-kD
`a-variant chain, noncovalently associated with a 29-kD P(cid:173)
`variant chain. The biologic role of the MHC molecules is to
`display antigenic peptides that enables appropriate TCRs to
`bind them. In general, class I MHC molecules present
`endogenously derived antigenic peptide after antigen process(cid:173)
`ing, such as viral epitopes, to CD8+ T cells, 15 whereas class II
`MHC molecules presen t exogenously derived antigenic
`peptide, such as soluble bacterial protein-derived antigenic
`peptide, to CD4+ T cells.16 Both class I and class II MHC
`gene products exhibit simple mendelian inheritance with
`co-dominant expressio n. Thus, single cells from any individ(cid:173)
`ual typically express pairs of the MHC gene products
`corresponding to the maternal and paternal alleles.
`Class I MHC molecules have three external domains, and
`their crystalline structure has been resolved. 17 The antigen(cid:173)
`binding site resides within a groove formed by the first and
`second (o:. 1 and o:.) external domains of the class I MHC mol(cid:173)
`ecule, and the appropriate TCR on CD8+ T cells recognizes
`the antigen in association with these epitopes; the o:.1 domain
`has been implicated in the interaction with CD8 (Figure 1-3).
`
`-+---- Peptide backbone
`([3-pleated sheet)
`
`- - - - - Anchor residue
`(binding amino acid)
`
`~ Groove (imagine
`cupped hand)
`
`FIGURE 1-3
`Floor of HLA class I molecule on antigen-presenting cell
`(APCJ. as seen by a CDS• T cell antigen receptor (TCR) complex. Tbe floor
`(groove) of the HLA class I molecule on an APC is formed by the ~-pleated
`sheets of the peptide backbone. Amino acids specific for each TCR complex
`anchor the two protein complexes in the presence of antigen. The TCR bind(cid:173)
`ing groove of HLA class II molecules binds to the CD4• of T cells in a sim(cid:173)
`ilar manner (see also Figure 1-4).
`
`On class II MHC molecules the o:. and~ chains each have two
`immunoglobulin-li ke ex ternal domains. The crystalline struc(cid:173)
`ture of class II molecules also has been determined, demon(cid:173)
`strating a putative antigen-binding cleft on the distal face of
`the molecule. 18 The appropriate TCR on CD4+ T cells recog(cid:173)
`nizes the antigen in this binding cleft, whereas the CD4 mol(cid:173)
`ecule binds to a nonpolymorphic epitope or epitopes on the
`class II MHC molecule. 19 Unlike antigenic peptides, certain
`microbial antigens referred to as superantigens can activate
`large numbers of T cells by direct interaction wi th class II
`MHC and the p chain of the TCR. Antigen induced activation
`of T cells requires a combination of two different signals.
`The first is provided by a TCR-based interaction between
`the receptor and the appropriate MHC-antigenic peptide.
`A second or co-stimulatory signal is required for antigen(cid:173)
`induced T cell activation, for example, the interaction
`between CD28 on the T cell and CD80 on the APC.
`Because generation of an effector immune response
`depends on helper T cell function, which is usually mediated
`by CD4+ T cell TCR recognition of an antigenic peptide pre(cid:173)
`sented in the groove of a class 11 MHC molecule, class II
`MHC molecules are referred to as the products of immune
`response genes. Thus the potential to mount an immune
`response depends on the class II MHC gene repertoire, as well
`as an appropri ate T cell receptor gene repertoire. Changes as
`subtle as a single amino acid difference at a critical site withi n
`the class II MHC molecule can alter its capacity to present an
`immunogenic peptide sequence derived from the intact anti(cid:173)
`gen. The described changes within class II MHC molecules
`associated with a responder or nonresponder state occur
`within the amino terminal domain that may translate into
`disease resistance or susceptibility. For example, disease
`resistance for juvenile-o nset diabetes can be conferred by
`having aspartate encoded at position 57 of a DQ p chain; this
`alters the salt bridge in the antigen-binding cleft of the DQ
`molecule. 20 Likewise, susceptibility for development of
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1022 - Page 7
`
`

`

`CHAPTER 1
`
`The Immune System
`
`5
`
`rheumatoid arthritis and pemphigus vulgaris is strongly asso(cid:173)
`ciated with particular class II MHC amino terminus residues.
`
`T Cell Antigen Receptor Gene Rearrangement
`and T Cell Activation
`The genes that encode the variable and constant regions of the
`TCR a and~ chains (or y and o) are found on separated DNA
`segments that must be rearranged for transcription of a com(cid:173)
`plete ribonucleic acid (RNA) message. The coding sequence
`of the variable (V) region of the a (and y) gene is formed by
`rearrangement of a V gene segment with a joining (J) gene
`segment, whereas V, diversity (D), and J gene segments of
`DNA reairnnge to produce~ (and o) chain variable region cod(cid:173)
`ing sequences. The V region sequences are next joined to the
`constant (C) region sequences. The net result of these DNA
`rearrangements and subsequent messenger RNA (mRNA)
`splicing during T cell development in the thymic cortex is to
`provide for an enormous diversity ofTCR antigen specificity.2 1
`
`When TCR-a~ binds to a specific peptide presented in the
`context of an appropriate MHC molecule in the presence of the
`co-stimulatory signal, a signal is imparted to the T cell that
`results in the following activation events: (1 ) hydrolysis of the
`phospholipid component of the lipid bilayer, phosphatidyl(cid:173)
`inositol bisphosphate, into inositol trisphosphate (IP3) and dia(cid:173)
`cylglycerol (DG); (2) elevation of intracellular calcium levels
`produced partly by IP,; (3) activation of protein kinase C
`(PKC) by interaction with DG; and (4) phosphorylation and
`activation of tyrosine kinase (Figure 1-4 ).22•23 All these activa(cid:173)
`tion events convey messages to the cell nucleus and appropri(cid:173)
`ate target genes for the nuclear factor of activated T cells
`(NFAT) and the protooncogene c-fos, or transcriptional regula(cid:173)
`tor proteins, such as activator protein-I (AP-1 ), that together
`regulate cell activity. These activated genes in tum code for
`proteins that commit the T cell to a subsequent specific
`function. Thus, there is an orderly appearance of proteins pro(cid:173)
`duced by the activated cell that are important in subsequent
`cell function or that interact with other immune cells.
`
`Antigen (AG)-presenting cell
`
`CDB0/86
`
`Class II MHC
`
`CD28
`
`Tcell
`
`Fyn or Lek
`phosphorylate
`tyrosine residues
`on the CD3 t and e
`c;haines, allowing
`ZAP-70, MAPK to
`bind and become
`activated
`
`. Fyn and Lek protein tyrosine kinase
`clustering activates kinase activity
`
`,--- ----< Protein tyrosine
`phosphatase
`activates
`Lek and Fyn
`
`1 - - -(cid:141) 1 ZAP-70 and Fyn kinases activate
`phospholipase C--y to cleave
`phosphatidylinositol to diacylglycerol
`(DAG) and inositol triphosphate (IP3)
`
`DAG activates protein kinase C (PKG)
`IP3 increases intracellular
`Ca2+ concentration
`
`PKC and Ca2+ activate other proteins(cid:173)
`ultimately a9tivating DNA-binding
`protei_ns (e.g. NF-KB, Oct, ETS)
`
`DNA-binding proteins induce specific
`gene tran~cription (NFAT, IL-2), leading
`to proliferation and differentiation
`
`FIGURE 1-4 Acti vation of CD4+ T cells, with binding of T cell antigen receptor (TCR) to antigen-presenting
`cell (first signal) and accessory molecul es (second signal). Cross-linking of TCR causes aggregation with the
`CD3 complex conta ining c, Ii, and t; chains, together with the three dimers and activation of phosphorylation and
`differe ntiation.
`ZAP, Zeta-associated protein; MHC, major histocompatibility complex; MAPK, mitogenic-associated prolifera(cid:173)
`tion kinase; NFAT, nuclear factor of activated T cells; IL, interle ukin; Lek, Fyn, tyrosine kinases.
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1022 - Page 8
`
`

`

`6
`
`SECT/ONA
`
`Immunology
`
`These intricate cell activation events are of considerable
`importance to the clinical practice of allergy and immunology
`because their discovery and e lucidation is helping explain
`mechanisms underl ying efficacious treatments given to
`patients for decades. Glucocorticoids, for example, inhibit
`early Teel I gene activation events by the induction of proteins
`that bind to DNA sequences in the region of promoter response
`elements, whereas cyclosporin A and tacrolimus (FK506)
`inhibit a serine/threonine-specific protein phosphatase called
`calcineurin that blocks specific gene transcription.
`
`B Cell Development
`The B cell matures in the bone marrow, but during fetal life
`this occurs in the liver. During maturation of the B cell, a
`series of DNA rearrangements of immunoglobulin heavy(cid:173)
`chain genes and light-chain genes occurs for production of
`membrane-bound and secreted immunoglobulin molecules
`(Table 1-2). As the pre-B cell matures, it acquires µ-chain
`gene rearrangement together with sun-ogate invariant light
`chains (11.5 and V pre-B) necessary for effective transport ofµ
`to the cell surface expressed as the pre- B cell receptor.
`Association of the pre-B cell receptor with lga and lg~ pro(cid:173)
`vides a means for signal transduction that facilitates contin(cid:173)
`ued maturation of the pre-B cell kappa (K) or lambda (A) gene
`rean-angements, ultimately resulting in the expression of a
`complete JgM molecule on the cell surface. Mature B cells
`coexpress surface IgM and lgD after heavy-chain mRNA
`splicing. All these maturation processes are antigen inde(cid:173)
`pendent. Subsequent differentiation of the IgM+/JgD+ mature
`B cells released into the periphery is antigen driven. Thus,
`activation of mature B cells into immunoglobulin-secreting B
`cells or long-lived memory B cells and final differen