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Chapter 25  Tolerance and Autoimmunity  293


            tolerance.  If  the  system  can  be  set  back  to  the  state  before  that   use immunomodulation to treat autoimmune diseases on the basis
            event, the disease could be cured. At present, it is unclear how to   of a better understanding of the pathogenesis.
            do  this;  however,  an  autologous  or  even  allogeneic  hematopoietic
            stem  cell  transplant  may  have  the  desired  effect.  In  fact,  this  sort
            of radical therapy has been tried in selected cases of severe SLE and   REFERENCES
            seems to have some efficacy. Another promising area is in channeling
            the  immune  response,  particularly  as  the  steering  mechanisms  are   1.  Nossal  GJ,  Pike  BL:  Mechanisms  of  clonal  abortion  tolerogenesis.
            becoming  better  understood  at  the  molecular  level.  A  third  area   I.  Response  of  immature  hapten-specific  B  lymphocytes.  J  Exp  Med
            is  to  design  more  specific  modulators  of  inflammation,  including   148:1161, 1978.
            interfering with costimulatory signals. These latter approaches have   2.  Nemazee DA, Burki K: Clonal deletion of B lymphocytes in a transgenic
            seemed  promising  in  various  animal  models,  although  issues  with   mouse bearing anti-MHC class I antibody genes. Nature 337:562, 1989.
            unexpected effects on clotting have arisen in clinical trials of CD40L     3.  Gay D, Saunders T, Camper S, et al: Receptor editing: an approach by
            inhibition.                                              autoreactive B cells to escape tolerance. J Exp Med 177(4):999–1008,
              Current therapy is much more crude and typically involves general   1993.
            nonspecific  immunosuppression  either  with  steroids  or  cytotoxic   4.  Tiegs SL, Russell DM, Nemazee D: Receptor editing in self-reactive bone
            drugs. Although these therapies can be effective, they have numerous   marrow B cells. J Exp Med 177(4):1009–1020, 1993.
            undesirable side effects, not the least of which is increased suscep-  5.  Sha  WC,  Nelson  CA,  Newberry  RD,  et al:  Positive  and  negative
            tibility to infection caused by immunosuppression. More promising   selection of an antigen receptor on T cells in transgenic mice. Nature
            are  drugs  such  as  monoclonal  antibodies  that  inhibit  the  effects   336(6194):73–76, 1988.
            of  specific  cytokines  such  as TNF-α,  which  have  proven  success-  6.  Kisielow P, Bluthmann H, Staerz UD, et al: Tolerance in T-cell-receptor
            ful  in  modifying  progression  of  RA,  inflammatory  bowel  disease,   transgenic mice involves deletion of nonmature CD4+8+ thymocytes.
            and  psoriasis.  Additionally,  the  injection  of  cytokines  themselves   Nature 333(6175):742–746, 1988.
            could also be effective at treating autoimmunity. For example, IL-2   7.  Anderson  MS,  Venanzi  ES,  Klein  L,  et al:  Projection  of  an  immu-
            administration  has  been  shown  to  expand  regulatory  T  cells  and   nological  self  shadow  within  the  thymus  by  the  aire  protein.  Science
            ameliorate disease in multiple autoimmune mouse models including   298(5597):1395–1401, 2002.
            type I diabetes and multiple sclerosis. In human clinical trials, IL-2   8.  Okamoto  M,  Murakami  M,  Shimizu  A,  et al:  A  transgenic  model  of
            was shown to be effective in reducing chronic GVHD. It would be   autoimmune hemolytic anemia. J Exp Med 175(1):71–79, 1992.
            interesting  to  see  if  IL-2  and  other  therapies  aimed  at  expanding   9.  Shlomchik  MJ,  Zharhary  D,  Saunders  T,  et al:  A  rheumatoid  factor
            regulatory  T  cells  will  be  an  effective  treatment  for  autoimmune     transgenic  mouse  model  of  autoantibody  regulation.  Int  Immunol
            disorders.                                               5(10):1329–1341, 1993.
              Reciprocally, therapies for autoimmune diseases in humans have   10.  Goodnow CC: Transgenic mice and analysis of B-cell tolerance. Annu
            in turn taught us new aspects of autoimmune disease pathogenesis.   Rev Immunol 10:489–518, 1992.
            A prime example of this is rituximab, which is a monoclonal anti-  11.  Mueller DL, Jenkins MK, Schwartz RH: Clonal expansion versus func-
                                                            +
            body that targets the CD20 antigen and hence depletes CD20  B   tional clonal inactivation: a costimulatory signalling pathway determines
                                                        +
            cells.  Rituximab  was  originally  developed  to  treat  CD20   B  cell   the outcome of T cell antigen receptor occupancy. Annu Rev Immunol
                      29
            malignancies,  but during clinical trials it was unexpectedly found   7:445–480, 1989.
            that cancer patients with concomitant RA showed improvement in   12.  Allen RC, Armitage RJ, Conley ME, et al: CD40 ligand gene defects
            their RA symptoms. This was surprising given that RA was thought   responsible for X-linked hyper-IgM syndrome. Science 259(5097):990–
            to be predominantly driven by T cells rather than by B cells. This   993, 1993.
            finding  prompted  clinical  trials  using  rituximab  for  the  treatment   13.  Leadbetter EA, Rifkin IR, Hohlbaum AM, et al: Chromatin-IgG com-
            of  a  number  of  autoimmune  diseases. These  include  autoimmune   plexes activate B cells by dual engagement of IgM and Toll-like receptors.
            diseases that are clearly antibody-mediated (e.g., ITP, AIHA, TTP,   Nature 416(6881):603–607, 2002.
            pemphigus vulgaris) but also include those that have less well-defined   14.  Inaba K, Witmer-Pack M, Inaba M, et al: The tissue distribution of the
            involvement of autoantibodies (e.g., vasculitides, multiple sclerosis,   B7-2 costimulator in mice: abundant expression on dendritic cells in situ
                            30
            RA, type I diabetes).  Although one might predict that rituximab   and during maturation in vitro. J Exp Med 180(5):1849–1860, 1994.
            attenuates autoimmunity by reducing autoantibody production by B   15.  Shlomchik MJ, Aucoin AH, Pisetsky DS, et al: Structure and function
            cells, this appears to not always be the case. For example, although   of anti-DNA autoantibodies derived from a single autoimmune mouse.
            clinically  effective,  rituximab  only  decreases  levels  of  RF  but  not   Proc Natl Acad Sci USA 84(24):9150–9154, 1987.
            of  anticitrullinated  peptide  antibodies  in  RA  patients.  Similarly,   16.  Crotty S: T follicular helper cell differentiation, function, and roles in
            antineutrophil cytoplasmic antibody (ANCA) levels are not decreased   disease. Immunity 41(4):529–542, 2014.
            in patients with ANCA-associated vasculitides treated with rituximab   17.  Watanabe-Fukunaga  R,  Brannan  CI,  Copeland  NG,  et al:  Lymphop-
            despite clinical efficacy. In fact, it is somewhat puzzling why ritux-  roliferation  disorder  in  mice  explained  by  defects  in  Fas  antigen  that
            imab would reduce circulating antibodies at all, given that CD20 is   mediates apoptosis. Nature 356(6367):314–317, 1992.
            expressed on mature B cells but not on plasma cells, which provide   18.  Suda T, Takahashi T, Golstein P, et al: Molecular cloning and expression
            the long-lasting source of autoantibodies in chronic autoimmunity.   of the Fas ligand, a novel member of the tumor necrosis factor family.
            Chronic treatment of patients with rituximab depletes memory and   Cell 75(6):1169–1178, 1993.
            activated  B  cells  that  repopulate  the  pool  of  plasma  cells  that  are   19.  Tivol  EA,  Borriello  F,  Schweitzer  AN,  et al:  Loss  of  CTLA-4  leads
            turning  over,  which  may  explain  why  circulating  antibody  levels   to  massive  lymphoproliferation  and  fatal  multiorgan  tissue  destruc-
            can  be  decreased.  However,  B-cell  depletion  by  rituximab  is  most   tion, revealing a critical negative regulatory role of CTLA-4. Immunity
            likely effective in many of these autoimmune disorders because of   3(5):541–547, 1995.
            the  antibody-independent  functions  of  B  cells  including  cytokine   20.  Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance
            production and antigen presentation.                     and immunity. Annu Rev Immunol 26:677–704, 2008.
              The therapeutic approaches discussed earlier, although a result of   21.  Zhu  J,  Yamane  H,  Paul  WE:  Differentiation  of  effector  CD4 T  cell
            modern biotechnology and our understanding of immunopathogen-  populations (*). Annu Rev Immunol 28:445–489, 2010.
            esis, still targets effector function of the immune system and does   22.  Asano M, Toda M, Sakaguchi N, et al: Autoimmune disease as a conse-
            not  modify  the  root  cause  of  disease. Therapies  should  ultimately   quence of developmental abnormality of a T cell subpopulation. J Exp
            be  directed  toward  either  prevention  or  else  specific  downregula-  Med 184(2):387–396, 1996.
            tion  of  ongoing  responses.  Future  work  will  include  continuing   23.  Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the develop-
            to  define  how  self-tolerance  is  imposed  and  how  it  is  broken  in   ment and function of CD4+CD25+ regulatory T cells. Nat Immunol
            disease, what the critical triggers and autoantigens are, and how to   4(4):330–336, 2003.
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