6 6 oumnal ofNeurology, Neurosurgery, and Psychiatry 1994;57 (Supplement):6-8 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.Suppl.6 on 1 November 1994. Downloaded from I FUNDAMENTALS

Immunomodulating effects of intravenous immunoglobulin in autoimmune and inflammatory diseases

Srinivas V Kaveri, Luc Mouthon, Michel D Kazatchkine

Intravenous immunoglobulin (IVIg) therapy and d) anti-D IgG induces an increase in is increasingly used for its immunomodulat- platelet counts in RhD-positive ITP patients.5 ing properties in a wide range of pathological Saturation of Fc receptors on splenic conditions including autoimmune diseases, is likely to play a critical role in systemic inflammatory diseases and allotrans- the beneficial effect of IVIg in peripheral plantation. Intravenous immunoglobulins are immune cytopenias. Another factor con- obtained from a pool of several thousand tributing to the beneficial effect of IVIg in healthy blood donors. They are composed of such diseases is idiotype-anti-idiotype inter- intact IgG with a distribution of subclasses acting, as shown in peripheral immune corresponding to that of normal serum and a thrombocytopenia with anti-GP Jib/lIla.6 half life of three weeks. IVIg represent a wide Basta et al observed a binding of IVIg to spectrum of natural and induced activated complement components C3b and activities which are present in normal human C4b, preventing them from binding to anti- serum, including directed against body-coated endothelial cells.7 Such binding external , and anti- results in solubilisation and dissociation of idiotypes.' This review will focus on the circulating immune complexes (CIC) follow- mechanisms by which infusion of normal ing IVIg therapy8 and protects guinea pigs human polyspecific IgG may be beneficial in from shock induced by lethal doses of anti- patients with autoimmune disorders. Forsmann antibodies.9 The effects of IVIg on NK cell activity have been assessed in patients with peripheral immune cytopenias Immunomodulating functions ofIVIg before and after treatment with IVIg. Clinical Immunomodulatory effects of IVIg may response and elevation of peripheral cell

depend on the interaction of infused IgG with counts were associated with a decrease in the http://jnnp.bmj.com/ inflammatory cells and through natural killer (NK) cell activity.'0 IVIg also Fc portions and/or interactions of IVIg with diminishes NK cell activity of healthy donors circulating immunoglobulins or in vitro in a dose-dependent pattern.'0 receptors on lymphocytes through variable (V) regions. To facilitate understanding of V REGION-DEPENDENT MECHANISMS OF the mechanisms of action of IVIg, we have ACTION OF IVIg them into three Idiotypic interactions between IVIg and divided groups: a) V-region on September 23, 2021 by guest. Protected copyright. dependent mechanisms, b) Fc-dependent autoantibodies mechanisms, and c) other mechanisms of The presence in IVIg of an anti-idiotypic action which include modulation of synthesis activity against disease-associated autoanti- and release of , interactions with bodies was first suggested by the rapid fall in surface molecules and modification lympho- the titre of anti-factor VIII autoantibodies in cyte population (table). The group may the plasma of patients with anti-factor VIII depend on both V region and Fc fraction of autoimmune disease treated with IVIg. We infused Ig. have now collected five lines of evidence to show that IVIg interacts through V regions FC DEPENDENT MECHANISMS OF ACTION OF with autoimmune disease-associated and with IVIg natural autoantibodies: Evidence for Fc-receptor blockade came from 1) F(ab'), fragments of IVIg neutralise the the following findings: a) administration of functional activity of autoantibodies and/or INSERM U28, Hopital Broussais, Rue Didot, IVIg is followed by a decrease in the clear- inhibit the binding of autoantibodies to Paris, France ance of autologous erythrocytes coated with autoantigens. S V Kaveri anti-D antibodies in vivo2; b) peripheral 2) Autoantibodies are specifically retained on L Mouthon M D Kazatchkine blood from IVIg-treated patients affinity chromatography columns of F(ab'), with ITP exhibit a decreased to form of to "' Correspondence to: ability fragments IVIg coupled Sepharose. Dr S V Kaveri, INSERM rosettes with IgG-coated erythrocytes in 3) Selective retention of autoantibodies on U 28, Hopital Broussais, vitro3; c) antibodies against FcyRIII show affinity columns of IVIg. 12 96 rue Didot, 75014 Paris, France. similar effects to those of IVIg in ITP in vivo4; 4) IVIg do not contain detectable antibodies Immunomodulating effects ofintravenous immunoglobulin (IVIg) in autoimmune and inflammatory diseases 7 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.Suppl.6 on 1 November 1994. Downloaded from Immunomodulating effects ofIVIg Functional modulation of T lymphocytes 1 Early effects ofIVIg infusion by IVIg has been demonstrated as another Neutralisation of circulating autoantibodies possible mechanism of action of IVIg in an Functional blockade of FcR on splenic macrophages Inhibition of complement-mediated damage experimental model where infusion of IVIg Changes in solubility and clearance of immune complexes resulted in the protection of Fl (Lewis Modulation of production of proinflammatory cytokines Phenotype changes on circulating leukocytes Brown-Norway) rats against the depen- 2 Long term effects ofIVIg infusion dent experimental model of autoimmune uve- Down regulation of IVIg-reactive clones and suppression of antibody synthesis oretinitis (EAU). Treatment with IVIg Stimulation of IVIg-reactive B cell clones decreased proliferative and anti- Alterations in spontaneous fluctuations of titres in serum body responses to S-Ag and the proliferative Selection ofT cell repertoires (?) response to Con A. Lymph node cells from Selection of functional T and B cell repertoires through changes in patterns of cytokines produced (?) IVIg-treated and S-Ag immunised animals Suppression of GVHD; suppression of alloantibodies neither proliferated nor secreted IL-2 in response to S-Ag but proliferated when cocultured with lymph node cells from rats immunised with S-Ag. These findings suggest peripheral anergy of T lymphocytes associ- ated with infusions of IVIg.25 against the Gml (3), Gml (4), Gml (17), Gml (1) and Km (1) allotypes that are most MODULATION OF THE RELEASE AND FUNCTION commonly expressed in the F(ab')2 region of OF PRO-INFL MATORY CYTOKINES BY IVIg human IgG.'3 Involvement of cytokines in systemic inflam- 5) IVIg share anti-idiotypic reactivity towards matory diseases and autoimmune disorders is idiotypes of autoantibodies with heterologous dependent on their ability to mediate and reg- anti-idiotypic antibodies. ulate inflammatory responses (for example, An analogy can be made between the interleukin-l (IL-1), IL-6, tumour necrosis recovery from autoimmune diseases using factor (TNF), IL-8, IL-10, IL-12 and IL-13), IVIg therapy and the spontaneous remission to regulate activation, growth and differentia- from autoimmune diseases which occurs in tion of lymphocytes (for example, IL-2, IL-4, association with the generation of auto-anti- IL-10, interferon (IFN)y and tumour growth idiotypic antibodies against prerecovery factor (TGF)ff) and to stimulate growth and autoantibodies. Anti-idiotypic antibodies differentiation of leukocytes in the bone mar- against autoantibodies have been found in row (colony stimulating factors, CSFs). We remission sera of patients with myasthenia have demonstrated that resolution of the gravis,'4 Guillain-Barre syndrome,'5 systemic inflammatory syndrome following infusion of vasculitis with ANCA autoantibodies,'6 sys- IVIg is associated with a somewhat paradoxi- temic lupus erythematosus,'7 anti-factor VIII cal dramatic decrease in the elevated serum autoimmune disease,'8 and anti-fibrinogen levels of IL-1 receptor antagonist (IL-i Ra) autoimmune disease.'9 In patients who spon- that are present before treatment.26 The pro- taneously recovered from anti-factor VIII tective effect of IVIg on coronary artery dam- autoimmune disease,'8 Guillain-Barre syn- age in Kawasaki syndrome could thus be drome'5 and in patients in remission from sys- related to decreased release and function of temic vasculitis with ANCA autoantibodies,'6 monocytic cytokines, decreased mononuclear http://jnnp.bmj.com/ we have observed that F(ab'), fragments of cell infiltration together with decreased anti- patients' post-recovery IgG inhibited autoan- body-mediated cell lysis. tibody activity in F(ab'), fragments of autolo- IVIg has also been shown to inhibit the gous IgG obtained during the acute phase of release of IL-1 and TNF from LPS-activated the disease. monocytes in vitro (Carreno, unpublished results) and has recently been shown to stim-

INTERACTION OF IVIg WITH T LYMPHOCYTES ulate the release of IL-1 Ra, from monocytes. on September 23, 2021 by guest. Protected copyright. The V region-dependent immunomodulatory Preliminary observations from our laboratory effects of IVIg cannot be restricted to the indicate that at least part of the effects of IVIg idiotypic-anti-idiotypic interactions between in inducing the natural IL-1 antagonist, IL- IVIg and autoantibodies and the B cell anti- IRa, from monocytes depends on the reactiv- gen receptor. There is evidence that IVIg ity of V regions of IVIg with membrane contains antibodies directed against constant molecules of monocytes.2' and variable regions of the fi chain of the T- We have recently analysed the changes that cell receptor20 and our own recent results occur in the expressed autoreactive antibody indicate the presence in IVIg of antibodies repertoire and in network organisation follow- reacting with CD5 and CD4.2'22 Preliminary ing the infusion of normal polyspecific IgG in evidence in vitro suggests that IVIg contains a patient with autoimmune thyroiditis.28 The antibodies reactive with V regions (idiotypes) results have enabled us to collect evidence of anti-class I and class II antibodies.23 indicating that changes in serum antibody Preliminary results using the synthetic pep- concentrations observed after infusion of IVIg tides B2702. 60-84 and LB5-77 derived from do not merely reflect passive transfer of IgG regions of the molecules involved in binding into the patient. The dynamic behaviour of to T cells24 indicate that IVIg contains anti- autoantibodies in the patient before infusion bodies reactive with these regions of HLA of immunoglobulin shows a clearly distinct molecules as assessed by ELISA (Kaveri and pattern with marked rhythmicity suggesting Glotz, unpublished observations). disruptions of connectivity within the 8 Kaven, Mouthon, Kazatchkine J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.Suppl.6 on 1 November 1994. Downloaded from immune network. Conversely, the kinetic pat- 13 Rossi F, Sultan Y, Kazatchkine MD. Anti-idiotypes against autoantibodies and alloantibodies to Factor tern after the infusion of IVIg is similar to VHIc (anti-hemophilic factor) are present in therapeutic that seen in healthy individuals. Thus infu- polyspecific normal immunoglobulins. Clin Exp Immunol 1988;74:31 1. sion of pooled normal immunoglobulin 14 Dwyer DS, Bradley RJ, Urquhart CK, Kearney JF. restored in the patient a network organisation Naturally occuning anti-idiotypic antibodies in myas- thenia gravis patients. Nature 1983;301:61 1. of autoantibodies characteristic of the physio- 15 Van Doom PA, Rossi F, Brand A, Van Lint M, logical conditions. Vermeulen M, Kazatchkine MD. On the mechanism of high dose intravenous immunoglobulin treatment of These observations support our hypothesis patients with chronic inflammatory demyelinating that the beneficial effect of IVIg in autoim- polyneuropathy with high-dose intravenous immuno- globulins. JNeuroimmunology 1990;29:57. mune diseases is not merely due to the pas- 16 Rossi F, Jayne DRW, Lockwood CM, Kazatchkine MD. sive transfer (transfusion) of neutralising Anti-idiotypes against anti- cytoplasmic anti- gen autoantibodies in normal human polyspecific IgG anti-idiotypic antibodies against autoantibod- for therapeutic use and in the remission serum of ies but that IVIg alters the structure and the patients with systemic vasculitis. Clin Exp Immunol 1991;83:298. dynamics of the idiotypic network in the 17 Zouali M, Eyquem A. Idiotypic/antiidiotypic interactions autoimmune patient to regain physiological in systemic lupus erythematosus: demonstration of oscillary levels of anti-DNA autoantibodies and recipro- control of . Thus IVIg would cal antiidiotypic activity in a single patient. Ann Immunol clearly differ in its mode of action from the (Inst Pasteur) 1983;134C:377. 18 Sultan Y, Rossi F, Kazatchkine MD. Recovery from anti- immunosuppressive approach to the treat- VIIc (anti-hemophilic factor) autoimmune disease is ment of autoimmune diseases.2930 dependent on generation of anti-idiotypes against anti- VHIc autoantibodies. Proc Nad Acad Sci (USA) 1987; 84:828. This work was supported by Institut National de la Sante et 19 Ruiz-Arguelles A. Spontaneous reversal of acquired de la Recherche Medicale (INSERM), Centre National de la autoimmune dysfibrinogenemia probably due to an anti- Recherche Scientifique (CNRS), France, the Central idiotypic antibody directed to an interspecies cross-reac- Laboratory of the Swiss Red Cross, Bern, Switzerland and tive idiotype expressed on antifibrinogen antibodies. J Baxter Healthcare Corporation, USA. Clin Invest 1988;82:958. 20 Marchalonis nl, Kaymaz H, Dedeoglu F, Schlutter SF, Yocum DE, Edmundson AB. Human autoantibodies 1 Rossi F, Dietrich G, Kazatchkine MD. Anti-idiotypes reactive with synthetic autoantigens from T-cell recep- against autoantibodies in normal immunoglobulins: tor ,B chain. Proc NadAcad Sci (USA) 1992;89:3325. Evidence for network regulation of human autoimmune 21 Vassilev T, Gelin C, Kaveri SV, Zilber MT, Boumsell L, responses. Immunol Rev 1989;110:135. Kazatchkine MD. Antibodies to the CD5 molecule in 2 Fehr J, Hofmann V, Kappeler U. Transient reversal of normal human immunoglobulins for therapeutic use thrombocytopenia in idiopathic thrombocytopenic pur- (Intravenous immunoglobulins, IVIg). Clin Exp Imm pura by high-dose intravenous gammaglobulin. N EngJ 1993;92:369. Med 1982;306: 1254. 22 Hurez V, Kaveri SV, Mouhoub A, Dietrich G, Mani JC, 3 Kimberly RP, Salmon JE, Bussel JB, Kuntz-Crow M, Klatzman D, Kazatchkine MD. Anti-CD4 activity of Hilgartner MW. Modulation of mononuclear normal human immunoglobulins G for therapeutic use function by intravenous gamma globulin. J Immunol (Intravenous immunoglobulin, IVIg). Therap Immunol 1984;132:745. 1994 (in press). 4 Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, 23 Atlas E, Freedman J, Blanchette V, Kazatchkine MD, Nachman RL, Unkeless JC. Treatment of refractory Semple JW. Down-regulation of the anti-HLLA alloim- immune thrombocytopenic purpura with an anti-Fc mune responses by variable region-reactive (anti-idio- gamma-receptor antibody. N Engl J Med 1986;314: typic) antibodies in leukemia patients with transfused 1236. with platelet concentrates. Blood 1992;81:538. 5 Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intra- 24 Clayberger C, Lyu SC, Pouletty P, Krensky AM. Peptides venous immunoglobulin in immune thrombocytopenia. corresponding to T-cell receptor-HIA contact regions Competitive inhibition of reticuloendothelial system inhibit class I-restricted immune responses. Transpl Proc function by sequestration of autologous red blood cells? 1993;25:477. Lancet 1983;ii:193. 25 Saoudi A, Hurez V, de Kozak Y, Kuhn J, Kaveri SV, 6 Berchtold P, Dale GL, Tani P, McMillan R. Inhibition of Kazatchkine MD, Druet P, Bellon B. Human autoantibody binding to platelet glycoprotein HIb/IIIa by immunoglobulin preparations for intravenous use anti-idiotypic antibodies in intravenous immunoglobu- (IVIg) prevent experimental autoimmune uveoretinitis. lins. Blood 1989;74:2414. Evidence for induction of anergy. Int Immunol 1993;

7 Basta M, Langlois PF, Marques M, Frank MM, Fries LF. 5:1559. http://jnnp.bmj.com/ High-dose intravenous immunoglobulin modifies com- 26 Ronda N, Ruiz De Souza V, Haeffner-Cavaillon N, plement-mediated in vivo clearance. Blood 1989;74:326. Kaveri SV, Kazatchkine MD, Shuiman SS. Rapid 8 Lin RY, Racis SP. In vivo reduction of circulating Clq decrease in circulating IL-1 receptor antagonist (IL-lra) binding immune complexes by intravenous gammaglob- after intravenous immunoglobulin therapy of Kawasaki ulin administration. Int Arch AUlergy Appl Immunol 1986; Disease. Unpublished observations. 79:286. 27 Ruiz de Souza V, Carreno MP, Haeffner-Cavaillon N, 9 Basta M, Kirshbom P, Frank MM, Fries LF. 1989. Kaveri SV, Kazatchkine MD. Induction of IL-receptor Mechanism of therapeutic effect of high-dose intra- antagonist by human immunoglobulins for intravenous venous immunoglobulin. Attenuation of acute, comple- use (WIg). EurJ7 Immunol (in press). ment-dependent immune damage in a guinea pig 28 Dietrich G, Varela F, Hurez V, Bouanani M, Kazatchkine

model. Clin Invest 1989;84: 1974. MD. Selection of the expressed B cell repertoire by on September 23, 2021 by guest. Protected copyright. 10 Engelhard D, Waner JL, Kapoor N, Good RA. Effect of infusion of normal in a patient with intravenous immune globulin on activ- autoimmune thyroiditis. EurJ Immunol 1993;23:2945. ity: Possible association with autoimmune neutropenia 29 Varela F, Andersson A, Dietrich G, Sundblad A, and idiopathic thrombocytopenia. J Pediatr 1986; Holmberg D, Kazatchkine MD, Coutinho A. The pop- 108:77. ulation dynamics of antibodies in normal and autoim- 11 Rossi F, Kazatchkine MD. Antiidiotypes against autoanti- mune individuals. Proc Nad Acad Sci (USA) 1991; bodies in pooled normal human polyspecific Ig. J 88:5917. Immunol 1989;143:4104. 30 Kaveri SV, Dietrich G, Ronda N, Hurez V, Ruiz de Souza 12 Ronda N, Haury M, Nobrega A, Coutinho A, V, Rowen D, Vassilev T, Kazatchkine MD. Suppression Kazatchkine MD. Selectivity of recognition of variable of autoimmunity through manipulation of immune net- (V) regions of autoantibodies by intravenous work with normal immunoglobulin G. In: Gergely J, ed. immunoglobulin (IVIg). Clin Immunol Immunopathol Progress in VIII. Berlin: Springer Verlag, 1994;70:124. 1993:643.