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Immunosuppressive therapy of autoimmune diseases
clinical perspectives 33 Springer,T.A. (1990) Nature 346, 425-434 34 Smith, D., Sanjar, S., Herd, C. and Morley,J. (1989) J. Pbarmacol Methods 21, 45-49 35 Sheffer,A.L. (1991)J. Allergy Clin. lmmunol. 88, 427-534 36 Gundei, R.H., Letts, L.G. and Gleich, G.J. (1991)J. Clin. Invest. 87, 1470--1473
37 jacoby, D.B. and Fryer, A.D. t1992)]. Clin. Invest. 90, 2292 38 Morley,J. (1991) in Preventive Therapy in Asthma (Morley, J., ed.), pp. 254-273, Academic Press 39 Hay, I.F. and Hlgenbottam, T.W. (1987) Lancet ii, 609-611 40 Townley,R.G. (1993)J. Lab. Clin. Med. 121, 15-17
Immunosuppressivetherapy of autoimmune diseases Jean-Franqois Bach Cyclosporin A, corticosteroids and cyclopbosphamide show a remarkable efficacy in a large number of autoimmune diseases. However, their effect is dependent on continuous drug administration with potential risks of drug toxicity and over immunosuppression. Results recently obtained in animal models, particularly with anti-CD3 and anti-CD4 monoclonal antibodies, indicate that reestablishment of tolerance to self antigens is a feasible goal. Autoimmune diseases are diverse and may involve most organs to various degrees. Although these diseases are of an immune nature their treatment has been, and often remains, essentially symptomatic (for example, substitutive hormones in autoimmune diseases of the endocrine glands and anti-inflammatory drugs in rheumatoid arthritis). Immunosuppressive treatment has been attempted in some autolmmune diseases. However, until 1980, success had usually been limited and the risk of side-effects was a major concern in diseases that are not usually life threatening. The discovery of new immunosuppressive drugs, especially cyclosporin A, and the emergence of immunologically active biological products (monoclond antibodies, cytokines and peptides) has dramatically changed the approach to the problem by showing that a number of diseases not previously thought to be of immune nature were ciinically improved by these agents. It is the aim of this review to present the state of the art and future perspectives of immunosuppression in autoimmunity. This article concentrates, at the clinical level, on the use of chemicals but mentions in detail the results obtained in various animal models of an autoimmune disease. The objectives There is much expectation that when a non-toxic and long-acting approach to mitigating autoimmune reactions becomes available, most if not all patients with autoimmune disease will be potential candidates for this new therapy. The number of diseases to be treated is very high (more than 40 such diseases have been identified) and the number of patients consider-
able. Such diseases are defined because of the pathogenetic effect of autoantibodies or autoreactive T cells. In some cases, the target autoantigen is determined, as in myasthenia gravis or Graves' disease. In other cases, the autoantigen is unknown or not precisely determined as in insulin dependent diabetes mellitus (IDDM) posing the question of the autoimmune nature of the disease as in psoriasis. In any case, autoimmune disease cannot be considered as a whole. Treatment selection must take into consideration a number of clinical parameters including the prognosis, the patient's age and the quality of a!ternative treatments. At the immunological level, there are three main questions. Is the disease B- or T-cell mediated? This is an important question since autoantibody formation and T-cell-mediated immunity do not have the same sensitivity to the various possible forms of immunointervention L2. The pathogenic role of autoantibodies is essentially suggested by disease transfer and, to a lesser degree, by correlations between the presence of the autoantibody and the disease activity. The problem is more complex for T-cell mediated disease; in the case of IDDM, T-cell transfer of the disease and its prevention by depletion or inactivation of T cells in animal models of the disease (NOD mouse and BB rat) are straightforward 3. In contrast, when there is no adequate spontaneous animal model one has to rely on more indirect evidence such as T-cell infiltration of the target organ or sensitivity to T-cell specific immunosuppressive agents such as cyclosporin (Table 1). Another important point to consider for antigen recognition-targeted intervention is the putative role of
© 1993, Elsevier Science Publishers Ltd, UK. 0167-5699/93/$06.00
Im,,unoto~ Today 3 2 2
Vol. ~4 No. 6 ~993
clinical perspectives Table 1. Differential sensitivity to immunosuppressive agents of antibody- and T-cell-mediated human autoimmune diseases Cyclophosphamide Antibody-mediated diseases Systemic lupus erythematosus Goodpasture's syndrome Wegener's granulomatosis Pemphigus
Cyclosperin
++ ++ ++ +
T-cell mediated diseases
Insulin dependent diabetes mellitus Uveitis Psoriasis
++ ++ +.t-
++: complete remission; +: partial remission;+: inconstant effect. the target autoantigen in driving the pathosenic autoimmune response. There is strong evidence for such a role in most organ-specific auto,immune disease. This includes hypermutation in the complementarity determining regions (CDRs) of autoantibody genes, HLAdisease association and elimination of autoimmune effectors by autoantigen removal in animal models 4. One should also consider the stage of the disease. Because of the fear of side-effects, it is usual to delay the start of immunosuppression for as long as possible. This is particularly the case in diseases with a slow or mild clinical course. It shnuld be stressed, however, that early immunointervention has major advantages and will become a priority when less toxic agents are available. First, the earlier the intervention, the more autoimmune damage can be avoided (which may be crucial in some diseases such as IDDM or multiple sclerosis (MS), in which the clinical diagnosis is made at a relatively late stage of anatomical progression). Secondly, there is evidence in spontaneous models of autoimmunity, such as IDDM and systemic lupus erythematosus (SLE), that early intervention is more efficient in reducing the intensity of the autoimmune response. Thus, NOD mice are only sensitive to a very limited number of immunosuppressive agents after the onset of overt diabetes (anti-CD3 (Ref. 5), anti-CD4 antibodies 6) or just before it (cyclosporinT). A number of other agents can prevent the disease when applied earlier (3--4 months of age); and still more numerous agents are effective when given in the first two months of life (intedeukin 1, various diets, etc.) (Table 2). Finally the objective of immunosuppression in autoimmune disease is to improve the clinical status by stopping or slowing the autoimmune response, without exposing the patient to unacceptable risks with regard to the disease prognosis (risk/benefit ratio) s. This objective has to be adapted to the nature of the disease and to the individual patient. Present status of treatment
The catalogue of immunosuppressive agents routinely used is essentially limited to five drugs or drug classes: steroids, azathioprine, cyclophosphamide, cyclosporin A and methotrexate, all of which have very different modes of action !.9. With a risk of oversimplification,
lmm,,,ology rod~y
one can say that at the dosages currently used, cyclophosphamide essentially acts on B cells while cyclospt, rin A and azathioprine act on T cells. For steroids and low-dose methotrexate ~° the situation is less clcar, especially as both agents show strong antiinflammatory properties. Extrapolating from the nature of the infections they promote and from in vitro data, it is assumed that steroids mainly act on macrophages but also on B and T cells at higher doses.
Antibody-mediated diseases Not surprisingly, steroids and cyclophosphamide show the greatest effects in these diseases. Remission of SLE, Wegener's granulomatosis and Goodpasture's syndrome can be obtained with cyc!ephosphamide ~'~2, and steroids show a remarkable effect on SLE, thus these drugs are very useful in treating autoimmune cytopenias. High doses of cyclophosphamide have been advocated in SLE but the superiority of this procedure over conventional regimens remains to be proven. Most pathogenic autoantibodies are of the IgG isotype and thus their generation is dependent on T-cell help, a situation which could explain the effect of azathioprine and cyclosporin A in some of these diseases. T-cell mediated diseases Cyclosporin A, the prototype T-cell selective agent, has a dramatic effect on a number of purportedly autoimmune diseases in the broad sense of the term (even when the antigen is not known or not proven to be a self antigen). This is the case for uveitis, IDDM, rheumatoid arthritis and primary biliary cirrhosis ~3. The drug is also active in other diseases in which its effects strongly suggest an immune (or autoimmune) nature, for example psoriaqis ~4, nephrotic syndrome ~, severe asthma 1~ or Crohn's disease ~. These are all diseases for which the evidence for autoimmune origin remains circumstantial. In some of these diseases lowdose methotrexate shows unquestionable efficacy, at least in cases of moderate severity (rheumatoid arthritis and psoriasis). Monoclonal anti-T-cell antibodies have been used in a limited series of patients with rheumatoid arthritis (RA) (anti-CD4), psoriasis (anti-CD4h MS (anti-CD4 and anti-CD3), and IDDM (anti-CD3). It is premature to interpret these data, which were obtained
323
Vo£ ~4 No. 6 ~993
clinical perspectives Table 2. Effects of various immunointervention procedures on the outcome of diabetes (as defined by hyperglycemia and glycosuria) in various settings (taken from Ref. 36) Stage of application ,:3 m
Cyclophosphamide induced IDDM
Overt diabetes
+ + +
+ ND ND
ND
+ + + ND
+ ND +
Anti-CD8 Anti-CD45A
+ +
÷
Anti-IFN-y
+
+
Chemicals Cyclosporin A FK506 Rapamycin Monoclonal antibodies Anti-CD3 Anti-TCR Anti-CD4 (depl) Anti-CD4 (non depl)
+ + + + (transfer) + (transfer) +
(transfer) Anti-MHC class II
+
ND
+
ND
ND
ND
+
+
+
ND
ND
÷ ÷ + +
ND ND ND ND
ND ND ND ND
+ +
ND ND
ND ND
+
ND
ND
+
ND
ND
T-cell vaccination IL-2 toxin Peptide therapy Miscellaneous Insulin Nicotinamide Poly l-Poly C LZ-8 immunomodulatory protein IL-I Complete Freund's adjuvant 1,25-dihydroxyvitamin D3 Diets (sorbose, casein,
Autoimmunity in the future
Drug resistance
gluten) +: prevention;ND: not done. in uncontrolled trials with the exception of psoriasis where dramatic remission of the disease was observed even in very severe forms.
Present limitations The spectacular effects referred to above should not make one forget the serious present limitations of immunosuppressive drugs in autoimmune disease. First, not all patients respond; in some diseases, such as MS, few patients respond to immunosuppression despite evidence of an underlying immune mechanism. Secondly, in most cases, the disease relapses a few months (sometimes a few weeks) after cessation of the treatment 13. This 'escape' is observed with all agents used so far, as if thest, drugs essentially act by 'freezing' the autoimmune reaction by reversibly inhibiting
Immunology today
B- or T-cell functions. One cannot rule out the possibility that the few cases in which the disease does not relapse correspond to a natural tendency for the disease to resolve spontaneously. This could occur because of the disappearance of the triggering factor, as exemplified by the long-term and often permanent remissions of rheumatic fever when one prevents the recurrence of streptococcal infections. This fear of relapse often leads to long-term treatment with an increased risk of toxicity and overimmunosuppression. Thirdly, all these agents have severe side-effects, especially when they are used for a long time at high doses. Combinations of several drugs (which are not often used in autoimmune disease because of the risk of over immunosuppression) have been used very successfully in organ transplantation by reducing the direct toxicity of individual drugs while maintaining the same overall efficacy. Such drug coinbinations could be used successfully in autoimmune disease if cautious monitoring is applied. Cyclosporin A-induced nephrotoxicity is rare and, apparently, always reversible. Functional and histological evidence suggests that this is the case when the dosage is kept below 5 mg/kg/day and patients are adequately monitored for creatininemia and blood pressure 1s'19. At this dosage cyclosporin (like low-dose methotrexate) does not promote opportunistic infections, perhaps because it acts se!ectively on primary immune responses and leaves secondary responses intact. The problem of malignancy probably warrants more concern, even if the risk is low (approximately one case per thousand) 13. Ideally, patients should not be treated for very long periods, even with these relatively low dosages. This risk also calls for careful clinical follow-up and early detection of the prelymphoma stage (pseudolymphoma) which often regresses when the treatment is stopped 2°.
Resistance of autoimmune disease to immunosuppressive drugs may have several explanations. In some cases, it may involve the drug dosage used, since not all autoimmune diseases are sensitive to the same dosage; cyclosporin is active in psoriasis at 3 mg/kg/day 14, in nephrotic syndrome at 5 mg/kg/day Is .A a,u only, at 6-7. . .m~!k~/dav in_c 21) and . , ~ , ~ - - , .in. . .I. ~. M ~,,.~,. uveitis. There may also be doubts as to the nature of the drug used or the autoimmune nature of the disease. Howevc:, two other major reasons usually explain such drug resistance. The first is the intensity of the autoimmune response, which renders it refractory to agents that if applied earlier, would have been efficacious. One approach to solving the problem is short-term use of agents known for their capacity to ameliorate hyperimmune responses (such as acute organ allograft rejection episodes). For instance, several autoimmune diseases (RA, psoriasis, Crohn's disease, MS) have recently been treated with anti-CD4 T-cell specific antibodies 22-zs or IL-2 toxin (RA, IDDM) z6. Alternatively, resistance may be linked to late intervention, when most of the target organ has been
324
VoL 14 No. 6 1993
clinical perspectives destroyed. For example, it is generally assumed that more than 80% of 13cells are destroyed when IDDM becomes clinically manifest. The solution to this is earlier diagnosis, not only by detecting early clinical and biological signs and symptoms but also by searching for genetic predisposing factors and early immunological markers of the autoimmune process before it has induced clinically detectable lesions. This approach has so far only been applied to IDDM but could be extrapolated to other autoimmune diseases. It should be realized, however, that the procedure is ethically acceptable only if treatment is safe, and this brings us back to the problem of toxicity.
30, 31; and see Adorini et al. this issue, pp. 285-289). Various monoclonal antibodies against, for example, adhesion molecules, could also be effective. Cytokines or anti-cytokines are another potential tool, as shown by the spectacular effect of anti-interferon gamma antibodies in murine SLE32, IDDM 33,34,uveitis, neuritis and adjuvant arthritis, and that of tumour necrosis factor in murine diabetes3s and SLE32.
Recurrence
Ideally, to avoid disease relapses at cessation of treatment, the etiologic factor dri,,ing the disease should be e!imina~ed. This is rarely possible (we have already cited the unique case of rheumatic fever); in most cases, a more accessible goal is probably re-establishment of the defective tolerance to the target self-antigen. One would like to use methods tested in experimental models such as soluble autoantigen 27 or autoantigen coupled to gammaglobulin. Unfortunately, one must recognize that the nature of the target autoantigen or epitope (B or T) is rarely known and one risks inducing the opposite effect, taking the form of a positive conventional immune response that would exacerbate the disease. Another, more attractive, approach is to attempt to induce tolerance without autoantigen administration under the assumption that the autoantigen is still present. This has recently been achieved successfully in the absence (perhaps mandatot3.') of other immunosuppressive treatments in overtly diabetic NOD mice using either antilymphocyte sera, a combination of anti-CD4 and anti-CD8 monoclonals 2~ or an anti-CD3 m. . . . clona! antibody 4. Perhaps the o,'al induction of T, 1-13mediated tolerance, which also does not require the knowledge of the target autoantigen, will give clinically useful results. The data obtained so far for EAE, uveitis and IDDM in NOD mice are indeed very promising-. •
"
')9
Hazards Direct drug toxicity is no longer, in our opinion, the major problem hampering the expansion of immunosuppressive therapy in autoimmune disease. Solutions should be found, however, to cyclosporin A nephroto×icity. The answer will probably not be provided by FK506, which has comparable nephrotoxicity at efficacious dosages. It is premature to comment on the presumably less nephrotoxic cyclosporin A analogs. Other drugs are available, including the various agents recently used in organ transplantation such as mycophenolic acid and brequinar Deoxyspergualin. Probably of more concern is the problem of long-term over immunosuppression. Again, the answer here may lie in strategies directed towards tolerance induction The use of agents more selective than those preseetly available could prove helpful until this goal is attained. In this context, at least for HLA-associated autoimmune disease, peptide therapy could be valuable, especially since preliminary results in mice are encouraging (Refs
lmmund.?Sy Ibday
Conclusions After the initial successes of steroids and cyclophosphamide, cyclosporin A has opened a new era of immunosuppression in autoimmunity by expanding significantly the field of its application. It must be hoped that all the new approaches recently developed in the laboratory will provide the means to reach the ultimate goal of early and safe induction of tolerance to the autoantigens that drive the undesired autoimmune responses at the origin of aatoimmune diseases. Jean-Francois Bach is at the Dept of Clinical Immunolo~:, Hfpita! Necker, 161 rue de Skvres, 75743 Paris, Cedex 15, France. References
1 Bach,J.F. and Strom, T.B. (198.5) The Mode of Action of !mmunosuppressive Agents, Elsevier SciencePublishers 2 Bach,J.F. and Feutren, G. (1985)in Ciclosporin in Autoimmune Diseases (Schindler, R., ed.), pp. 33-38, Springer Verlag 3 Honeyman,M.C. and Harrison, L.C. (1993)Sernin. Immunopathol. 14, 253-274 4 Roitt, I.M. et al. (1992)J. Autoimmunity 5 (Suppl. A), 11-26
5 Chatenoud, L., Thervet, E., Primo, J. and Bach, J.F. (1992) C. R. Acad. Sci. Paris 315, 22~-228 6 Hutchings,P., O'Reiily, L., Parish, N.M., Waldmann, H. and Cooke, A. (1992) Eur. ]. immunoi. 22, i9i3-1918 7 Mori, Y. et al. (1986) Diabetologia 29, 244-247 8 Bach,J.F. (1992)]. Autoimmunity S (Suppl. A), 3-10 9 Rugstad, H.E., Endresen, L. and Forre, O. (1992) Immunopharmacology in Autoimmune Diseases and Transplantation, Plenum Press 10 Endresen, L. (1992)in Immunopharmacology in Autoimmune Diseases and Transplantation (Rugstad, H.E.,
Endresen. L. and Forre, O., eds), pp. 127-138, Plenum Press 11 Austin,H.A., III et al. (1986) New Engl. J. Med. 314, 614-619 12 Fau,., A.S., Haynes, B.F., Katz, P. and Wolff, S.M. (1983) Ann. Intern. Med. 98, 76-85 13 Feutren, G. and yon Graffenried, B. (1992)in Immunopharmacology in Autoimmune Diseases and Transplantation (Rugstad, H.E., Endresen, L. and Forte, O.,
eds), pp. 159-173, Plenum Press 14 Ellis, C.N. et a!. (199!) New Engl. J. Med. 324, 277-284 15 Meyrier,A. (1989) Nephrol. Dial. Transplant. 4, 923-931 16 Alexander, A.G., Barnes, N.C. and Kay, A.B. (1992) Lancet 339, 324-328 17 Brynskov,J. et al. (1989) New Engl. J. Med. 321,845-850 18 Feutren, G. and Mihatsch, M.J. (1992) New Engl. J. Med. 326, 1654-1660 19 Assan, R. et al. Clin. Nepbrol. (in press) 20 Starzl,T.E. et al. (1984) Lancet i, 583-587 21 Feutren, G. etal. (1986) Lancet ii, 119-124 22 Riethmidler, G. et al. (1992) lmmunol. Rev. 129, 81-104 23 Goldberg, D. et al. (1991)J. Autoimrnunity 4, 617-630 24 Nicolas,J.F. et al. (1992) Lancet 338, 321
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Vol. 14 No. 61993
clinical perspectives 25 Steinman, L., Lindsey, J.W., Alters, S. and Hodgkinson, S. (1993) in MonoclonalAntibody and PeptideTherapy in Autoimmune Diseases(Bach, J.F., ed.), pp. 253-260, Marcel Dekker 26 Strom, T.B., Kelley, V.R., Woodworth, T.G. and Murphy, J.R. (1992) lmmunol. Rev. 129, 131-163 27 Rayner, D.C., Champion, B.R. and Cooke, A. (1993) in MonoclonalAntibody and Peptide Therapyin Autoimmune Diseases(]~ach,J.F., ed.), pp. 359-375, Marcel Dekker 28 Maki, T., Ichikawa, T., Blanco, R. and Porter, J. (1992) Proc. Natl Acad. Sci. USA 89, 3434-3438 29 Miller, A., Lider, O. and Weiner, H.L. (1991)J. Exp. Med. 174, 791-798
30 Wraith, D.C., Smilek, D.E. and Webb, S. (1992)
J. Autoimmuni~y5 (Suppl. A), 103-113 31 Rothbard, J.B. and McDevitt, H.O. (1993) in T-cell DirectedImmunointervention (Bach, J.F., ed.), pp. 286-299, Blackwell Scientific Publications 32 Jacob, C.O., van der Meide, P.H. and McDevitt, H.O. (1987)J. Exp. Med. 166, 798-803 33 Debray-Sachs, M. et al. (1991)J. Autoimmunity 4, 237-248 34 Campbell, I.L., Kay, T.W.H., Oxbrow, L. and Harrison, L.C. (1991)J. Clin. Invest. 87, 739-742 35 Jacob, C.O., Aiso, S., Michie, S.A., McDevitt, H.O. and Acha-Orbea, H. (1992) Immunology 87, 968-972 36 Bach, J.F. Ann. N. Y. Acad. Sci. (in press)
D.onor cell chimerism permitted by mmunosuppressive drugs: a new view of organ transplantation Thomas E. Starzl, Anthony J. Demetris, Noriko Murase, Angus W. Thomson, Massimo Trucco and Camillo Ricordi One line of thought in organ transplantation feels that immunosuppressive drugs can lead to tolerance induction by allowing a previously unrecognized common mechanism of cell migration and microcbimerism to occur, persist, and in some cases, become drug independent. It has been recognized that there is a spectrum of susceptibility of different organs to cellular rejection and that the variable ability of these organs to induce donorspecific nonreactivity reflects their comparative content of migratory leukocytes. Here, Thomas Starzl and colleagues discuss bow many of the enigmas of transplantation immunology can be explained by this cbimerism. The prevention of organ rejection by various immunosuppressive agents has been described increasingly in terms of tbe molecular site of disruption of the alloactivated T-cell response ~,2. Recent evidence, however, suggests that the control of rejection and, ultimately, graft acceptance depend on a permissive effect of these drugs on a mutual host--graft leukocyte rn;granon that leads in successful cases to mixed, long-term microchimerism in the recipient as well as the transplant 3(Fig. 1). An empiric drug regimen Observations compatible with this concept were reported in 1963 when combination therapy with azathioprine and prednisone was introduced for kidney transplantation 4. There is a characteristic cycle of renal graft rejection in the first few days or weeks that can be reversed with steroids. The ability to reduce (Fig. 2), or sometimes even to stop, treatment was thereafter
confirmed in cases of transplantation of the liver, heart and other organs. The reproducibility of these events led to the fundamental therapeutic dogma that forms the basis of whole organ transplantation surgery. It calls for daily baseline treatment with a maintenance drug or drugs (originally azathioprine) plus trial and error intervention with the highly dose-manouverable adrenal cortical steroids, along with anti-lymphoid agents to whatever level is required to maintain stable graft function. Throughout the years, this policy framework has accommodated increasingly potent new agents with variable sites of action (Table 1). The chimeric host and graft Under the regimes described above it became evident that something, not drug specific, appeared to have changed in either the graft, the recipient or both. But what?
© 1993, ElsevierSciencePublishersLtd, UK. 0167-5699/931506.00
Immunology Today
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Vol. 14 No. 6 1993
37 jacoby, D.B. and Fryer, A.D. t1992)]. Clin. Invest. 90, 2292 38 Morley,J. (1991) in Preventive Therapy in Asthma (Morley, J., ed.), pp. 254-273, Academic Press 39 Hay, I.F. and Hlgenbottam, T.W. (1987) Lancet ii, 609-611 40 Townley,R.G. (1993)J. Lab. Clin. Med. 121, 15-17
Immunosuppressivetherapy of autoimmune diseases Jean-Franqois Bach Cyclosporin A, corticosteroids and cyclopbosphamide show a remarkable efficacy in a large number of autoimmune diseases. However, their effect is dependent on continuous drug administration with potential risks of drug toxicity and over immunosuppression. Results recently obtained in animal models, particularly with anti-CD3 and anti-CD4 monoclonal antibodies, indicate that reestablishment of tolerance to self antigens is a feasible goal. Autoimmune diseases are diverse and may involve most organs to various degrees. Although these diseases are of an immune nature their treatment has been, and often remains, essentially symptomatic (for example, substitutive hormones in autoimmune diseases of the endocrine glands and anti-inflammatory drugs in rheumatoid arthritis). Immunosuppressive treatment has been attempted in some autolmmune diseases. However, until 1980, success had usually been limited and the risk of side-effects was a major concern in diseases that are not usually life threatening. The discovery of new immunosuppressive drugs, especially cyclosporin A, and the emergence of immunologically active biological products (monoclond antibodies, cytokines and peptides) has dramatically changed the approach to the problem by showing that a number of diseases not previously thought to be of immune nature were ciinically improved by these agents. It is the aim of this review to present the state of the art and future perspectives of immunosuppression in autoimmunity. This article concentrates, at the clinical level, on the use of chemicals but mentions in detail the results obtained in various animal models of an autoimmune disease. The objectives There is much expectation that when a non-toxic and long-acting approach to mitigating autoimmune reactions becomes available, most if not all patients with autoimmune disease will be potential candidates for this new therapy. The number of diseases to be treated is very high (more than 40 such diseases have been identified) and the number of patients consider-
able. Such diseases are defined because of the pathogenetic effect of autoantibodies or autoreactive T cells. In some cases, the target autoantigen is determined, as in myasthenia gravis or Graves' disease. In other cases, the autoantigen is unknown or not precisely determined as in insulin dependent diabetes mellitus (IDDM) posing the question of the autoimmune nature of the disease as in psoriasis. In any case, autoimmune disease cannot be considered as a whole. Treatment selection must take into consideration a number of clinical parameters including the prognosis, the patient's age and the quality of a!ternative treatments. At the immunological level, there are three main questions. Is the disease B- or T-cell mediated? This is an important question since autoantibody formation and T-cell-mediated immunity do not have the same sensitivity to the various possible forms of immunointervention L2. The pathogenic role of autoantibodies is essentially suggested by disease transfer and, to a lesser degree, by correlations between the presence of the autoantibody and the disease activity. The problem is more complex for T-cell mediated disease; in the case of IDDM, T-cell transfer of the disease and its prevention by depletion or inactivation of T cells in animal models of the disease (NOD mouse and BB rat) are straightforward 3. In contrast, when there is no adequate spontaneous animal model one has to rely on more indirect evidence such as T-cell infiltration of the target organ or sensitivity to T-cell specific immunosuppressive agents such as cyclosporin (Table 1). Another important point to consider for antigen recognition-targeted intervention is the putative role of
© 1993, Elsevier Science Publishers Ltd, UK. 0167-5699/93/$06.00
Im,,unoto~ Today 3 2 2
Vol. ~4 No. 6 ~993
clinical perspectives Table 1. Differential sensitivity to immunosuppressive agents of antibody- and T-cell-mediated human autoimmune diseases Cyclophosphamide Antibody-mediated diseases Systemic lupus erythematosus Goodpasture's syndrome Wegener's granulomatosis Pemphigus
Cyclosperin
++ ++ ++ +
T-cell mediated diseases
Insulin dependent diabetes mellitus Uveitis Psoriasis
++ ++ +.t-
++: complete remission; +: partial remission;+: inconstant effect. the target autoantigen in driving the pathosenic autoimmune response. There is strong evidence for such a role in most organ-specific auto,immune disease. This includes hypermutation in the complementarity determining regions (CDRs) of autoantibody genes, HLAdisease association and elimination of autoimmune effectors by autoantigen removal in animal models 4. One should also consider the stage of the disease. Because of the fear of side-effects, it is usual to delay the start of immunosuppression for as long as possible. This is particularly the case in diseases with a slow or mild clinical course. It shnuld be stressed, however, that early immunointervention has major advantages and will become a priority when less toxic agents are available. First, the earlier the intervention, the more autoimmune damage can be avoided (which may be crucial in some diseases such as IDDM or multiple sclerosis (MS), in which the clinical diagnosis is made at a relatively late stage of anatomical progression). Secondly, there is evidence in spontaneous models of autoimmunity, such as IDDM and systemic lupus erythematosus (SLE), that early intervention is more efficient in reducing the intensity of the autoimmune response. Thus, NOD mice are only sensitive to a very limited number of immunosuppressive agents after the onset of overt diabetes (anti-CD3 (Ref. 5), anti-CD4 antibodies 6) or just before it (cyclosporinT). A number of other agents can prevent the disease when applied earlier (3--4 months of age); and still more numerous agents are effective when given in the first two months of life (intedeukin 1, various diets, etc.) (Table 2). Finally the objective of immunosuppression in autoimmune disease is to improve the clinical status by stopping or slowing the autoimmune response, without exposing the patient to unacceptable risks with regard to the disease prognosis (risk/benefit ratio) s. This objective has to be adapted to the nature of the disease and to the individual patient. Present status of treatment
The catalogue of immunosuppressive agents routinely used is essentially limited to five drugs or drug classes: steroids, azathioprine, cyclophosphamide, cyclosporin A and methotrexate, all of which have very different modes of action !.9. With a risk of oversimplification,
lmm,,,ology rod~y
one can say that at the dosages currently used, cyclophosphamide essentially acts on B cells while cyclospt, rin A and azathioprine act on T cells. For steroids and low-dose methotrexate ~° the situation is less clcar, especially as both agents show strong antiinflammatory properties. Extrapolating from the nature of the infections they promote and from in vitro data, it is assumed that steroids mainly act on macrophages but also on B and T cells at higher doses.
Antibody-mediated diseases Not surprisingly, steroids and cyclophosphamide show the greatest effects in these diseases. Remission of SLE, Wegener's granulomatosis and Goodpasture's syndrome can be obtained with cyc!ephosphamide ~'~2, and steroids show a remarkable effect on SLE, thus these drugs are very useful in treating autoimmune cytopenias. High doses of cyclophosphamide have been advocated in SLE but the superiority of this procedure over conventional regimens remains to be proven. Most pathogenic autoantibodies are of the IgG isotype and thus their generation is dependent on T-cell help, a situation which could explain the effect of azathioprine and cyclosporin A in some of these diseases. T-cell mediated diseases Cyclosporin A, the prototype T-cell selective agent, has a dramatic effect on a number of purportedly autoimmune diseases in the broad sense of the term (even when the antigen is not known or not proven to be a self antigen). This is the case for uveitis, IDDM, rheumatoid arthritis and primary biliary cirrhosis ~3. The drug is also active in other diseases in which its effects strongly suggest an immune (or autoimmune) nature, for example psoriaqis ~4, nephrotic syndrome ~, severe asthma 1~ or Crohn's disease ~. These are all diseases for which the evidence for autoimmune origin remains circumstantial. In some of these diseases lowdose methotrexate shows unquestionable efficacy, at least in cases of moderate severity (rheumatoid arthritis and psoriasis). Monoclonal anti-T-cell antibodies have been used in a limited series of patients with rheumatoid arthritis (RA) (anti-CD4), psoriasis (anti-CD4h MS (anti-CD4 and anti-CD3), and IDDM (anti-CD3). It is premature to interpret these data, which were obtained
323
Vo£ ~4 No. 6 ~993
clinical perspectives Table 2. Effects of various immunointervention procedures on the outcome of diabetes (as defined by hyperglycemia and glycosuria) in various settings (taken from Ref. 36) Stage of application ,:3 m
Cyclophosphamide induced IDDM
Overt diabetes
+ + +
+ ND ND
ND
+ + + ND
+ ND +
Anti-CD8 Anti-CD45A
+ +
÷
Anti-IFN-y
+
+
Chemicals Cyclosporin A FK506 Rapamycin Monoclonal antibodies Anti-CD3 Anti-TCR Anti-CD4 (depl) Anti-CD4 (non depl)
+ + + + (transfer) + (transfer) +
(transfer) Anti-MHC class II
+
ND
+
ND
ND
ND
+
+
+
ND
ND
÷ ÷ + +
ND ND ND ND
ND ND ND ND
+ +
ND ND
ND ND
+
ND
ND
+
ND
ND
T-cell vaccination IL-2 toxin Peptide therapy Miscellaneous Insulin Nicotinamide Poly l-Poly C LZ-8 immunomodulatory protein IL-I Complete Freund's adjuvant 1,25-dihydroxyvitamin D3 Diets (sorbose, casein,
Autoimmunity in the future
Drug resistance
gluten) +: prevention;ND: not done. in uncontrolled trials with the exception of psoriasis where dramatic remission of the disease was observed even in very severe forms.
Present limitations The spectacular effects referred to above should not make one forget the serious present limitations of immunosuppressive drugs in autoimmune disease. First, not all patients respond; in some diseases, such as MS, few patients respond to immunosuppression despite evidence of an underlying immune mechanism. Secondly, in most cases, the disease relapses a few months (sometimes a few weeks) after cessation of the treatment 13. This 'escape' is observed with all agents used so far, as if thest, drugs essentially act by 'freezing' the autoimmune reaction by reversibly inhibiting
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B- or T-cell functions. One cannot rule out the possibility that the few cases in which the disease does not relapse correspond to a natural tendency for the disease to resolve spontaneously. This could occur because of the disappearance of the triggering factor, as exemplified by the long-term and often permanent remissions of rheumatic fever when one prevents the recurrence of streptococcal infections. This fear of relapse often leads to long-term treatment with an increased risk of toxicity and overimmunosuppression. Thirdly, all these agents have severe side-effects, especially when they are used for a long time at high doses. Combinations of several drugs (which are not often used in autoimmune disease because of the risk of over immunosuppression) have been used very successfully in organ transplantation by reducing the direct toxicity of individual drugs while maintaining the same overall efficacy. Such drug coinbinations could be used successfully in autoimmune disease if cautious monitoring is applied. Cyclosporin A-induced nephrotoxicity is rare and, apparently, always reversible. Functional and histological evidence suggests that this is the case when the dosage is kept below 5 mg/kg/day and patients are adequately monitored for creatininemia and blood pressure 1s'19. At this dosage cyclosporin (like low-dose methotrexate) does not promote opportunistic infections, perhaps because it acts se!ectively on primary immune responses and leaves secondary responses intact. The problem of malignancy probably warrants more concern, even if the risk is low (approximately one case per thousand) 13. Ideally, patients should not be treated for very long periods, even with these relatively low dosages. This risk also calls for careful clinical follow-up and early detection of the prelymphoma stage (pseudolymphoma) which often regresses when the treatment is stopped 2°.
Resistance of autoimmune disease to immunosuppressive drugs may have several explanations. In some cases, it may involve the drug dosage used, since not all autoimmune diseases are sensitive to the same dosage; cyclosporin is active in psoriasis at 3 mg/kg/day 14, in nephrotic syndrome at 5 mg/kg/day Is .A a,u only, at 6-7. . .m~!k~/dav in_c 21) and . , ~ , ~ - - , .in. . .I. ~. M ~,,.~,. uveitis. There may also be doubts as to the nature of the drug used or the autoimmune nature of the disease. Howevc:, two other major reasons usually explain such drug resistance. The first is the intensity of the autoimmune response, which renders it refractory to agents that if applied earlier, would have been efficacious. One approach to solving the problem is short-term use of agents known for their capacity to ameliorate hyperimmune responses (such as acute organ allograft rejection episodes). For instance, several autoimmune diseases (RA, psoriasis, Crohn's disease, MS) have recently been treated with anti-CD4 T-cell specific antibodies 22-zs or IL-2 toxin (RA, IDDM) z6. Alternatively, resistance may be linked to late intervention, when most of the target organ has been
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clinical perspectives destroyed. For example, it is generally assumed that more than 80% of 13cells are destroyed when IDDM becomes clinically manifest. The solution to this is earlier diagnosis, not only by detecting early clinical and biological signs and symptoms but also by searching for genetic predisposing factors and early immunological markers of the autoimmune process before it has induced clinically detectable lesions. This approach has so far only been applied to IDDM but could be extrapolated to other autoimmune diseases. It should be realized, however, that the procedure is ethically acceptable only if treatment is safe, and this brings us back to the problem of toxicity.
30, 31; and see Adorini et al. this issue, pp. 285-289). Various monoclonal antibodies against, for example, adhesion molecules, could also be effective. Cytokines or anti-cytokines are another potential tool, as shown by the spectacular effect of anti-interferon gamma antibodies in murine SLE32, IDDM 33,34,uveitis, neuritis and adjuvant arthritis, and that of tumour necrosis factor in murine diabetes3s and SLE32.
Recurrence
Ideally, to avoid disease relapses at cessation of treatment, the etiologic factor dri,,ing the disease should be e!imina~ed. This is rarely possible (we have already cited the unique case of rheumatic fever); in most cases, a more accessible goal is probably re-establishment of the defective tolerance to the target self-antigen. One would like to use methods tested in experimental models such as soluble autoantigen 27 or autoantigen coupled to gammaglobulin. Unfortunately, one must recognize that the nature of the target autoantigen or epitope (B or T) is rarely known and one risks inducing the opposite effect, taking the form of a positive conventional immune response that would exacerbate the disease. Another, more attractive, approach is to attempt to induce tolerance without autoantigen administration under the assumption that the autoantigen is still present. This has recently been achieved successfully in the absence (perhaps mandatot3.') of other immunosuppressive treatments in overtly diabetic NOD mice using either antilymphocyte sera, a combination of anti-CD4 and anti-CD8 monoclonals 2~ or an anti-CD3 m. . . . clona! antibody 4. Perhaps the o,'al induction of T, 1-13mediated tolerance, which also does not require the knowledge of the target autoantigen, will give clinically useful results. The data obtained so far for EAE, uveitis and IDDM in NOD mice are indeed very promising-. •
"
')9
Hazards Direct drug toxicity is no longer, in our opinion, the major problem hampering the expansion of immunosuppressive therapy in autoimmune disease. Solutions should be found, however, to cyclosporin A nephroto×icity. The answer will probably not be provided by FK506, which has comparable nephrotoxicity at efficacious dosages. It is premature to comment on the presumably less nephrotoxic cyclosporin A analogs. Other drugs are available, including the various agents recently used in organ transplantation such as mycophenolic acid and brequinar Deoxyspergualin. Probably of more concern is the problem of long-term over immunosuppression. Again, the answer here may lie in strategies directed towards tolerance induction The use of agents more selective than those preseetly available could prove helpful until this goal is attained. In this context, at least for HLA-associated autoimmune disease, peptide therapy could be valuable, especially since preliminary results in mice are encouraging (Refs
lmmund.?Sy Ibday
Conclusions After the initial successes of steroids and cyclophosphamide, cyclosporin A has opened a new era of immunosuppression in autoimmunity by expanding significantly the field of its application. It must be hoped that all the new approaches recently developed in the laboratory will provide the means to reach the ultimate goal of early and safe induction of tolerance to the autoantigens that drive the undesired autoimmune responses at the origin of aatoimmune diseases. Jean-Francois Bach is at the Dept of Clinical Immunolo~:, Hfpita! Necker, 161 rue de Skvres, 75743 Paris, Cedex 15, France. References
1 Bach,J.F. and Strom, T.B. (198.5) The Mode of Action of !mmunosuppressive Agents, Elsevier SciencePublishers 2 Bach,J.F. and Feutren, G. (1985)in Ciclosporin in Autoimmune Diseases (Schindler, R., ed.), pp. 33-38, Springer Verlag 3 Honeyman,M.C. and Harrison, L.C. (1993)Sernin. Immunopathol. 14, 253-274 4 Roitt, I.M. et al. (1992)J. Autoimmunity 5 (Suppl. A), 11-26
5 Chatenoud, L., Thervet, E., Primo, J. and Bach, J.F. (1992) C. R. Acad. Sci. Paris 315, 22~-228 6 Hutchings,P., O'Reiily, L., Parish, N.M., Waldmann, H. and Cooke, A. (1992) Eur. ]. immunoi. 22, i9i3-1918 7 Mori, Y. et al. (1986) Diabetologia 29, 244-247 8 Bach,J.F. (1992)]. Autoimmunity S (Suppl. A), 3-10 9 Rugstad, H.E., Endresen, L. and Forre, O. (1992) Immunopharmacology in Autoimmune Diseases and Transplantation, Plenum Press 10 Endresen, L. (1992)in Immunopharmacology in Autoimmune Diseases and Transplantation (Rugstad, H.E.,
Endresen. L. and Forre, O., eds), pp. 127-138, Plenum Press 11 Austin,H.A., III et al. (1986) New Engl. J. Med. 314, 614-619 12 Fau,., A.S., Haynes, B.F., Katz, P. and Wolff, S.M. (1983) Ann. Intern. Med. 98, 76-85 13 Feutren, G. and yon Graffenried, B. (1992)in Immunopharmacology in Autoimmune Diseases and Transplantation (Rugstad, H.E., Endresen, L. and Forte, O.,
eds), pp. 159-173, Plenum Press 14 Ellis, C.N. et a!. (199!) New Engl. J. Med. 324, 277-284 15 Meyrier,A. (1989) Nephrol. Dial. Transplant. 4, 923-931 16 Alexander, A.G., Barnes, N.C. and Kay, A.B. (1992) Lancet 339, 324-328 17 Brynskov,J. et al. (1989) New Engl. J. Med. 321,845-850 18 Feutren, G. and Mihatsch, M.J. (1992) New Engl. J. Med. 326, 1654-1660 19 Assan, R. et al. Clin. Nepbrol. (in press) 20 Starzl,T.E. et al. (1984) Lancet i, 583-587 21 Feutren, G. etal. (1986) Lancet ii, 119-124 22 Riethmidler, G. et al. (1992) lmmunol. Rev. 129, 81-104 23 Goldberg, D. et al. (1991)J. Autoimrnunity 4, 617-630 24 Nicolas,J.F. et al. (1992) Lancet 338, 321
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clinical perspectives 25 Steinman, L., Lindsey, J.W., Alters, S. and Hodgkinson, S. (1993) in MonoclonalAntibody and PeptideTherapy in Autoimmune Diseases(Bach, J.F., ed.), pp. 253-260, Marcel Dekker 26 Strom, T.B., Kelley, V.R., Woodworth, T.G. and Murphy, J.R. (1992) lmmunol. Rev. 129, 131-163 27 Rayner, D.C., Champion, B.R. and Cooke, A. (1993) in MonoclonalAntibody and Peptide Therapyin Autoimmune Diseases(]~ach,J.F., ed.), pp. 359-375, Marcel Dekker 28 Maki, T., Ichikawa, T., Blanco, R. and Porter, J. (1992) Proc. Natl Acad. Sci. USA 89, 3434-3438 29 Miller, A., Lider, O. and Weiner, H.L. (1991)J. Exp. Med. 174, 791-798
30 Wraith, D.C., Smilek, D.E. and Webb, S. (1992)
J. Autoimmuni~y5 (Suppl. A), 103-113 31 Rothbard, J.B. and McDevitt, H.O. (1993) in T-cell DirectedImmunointervention (Bach, J.F., ed.), pp. 286-299, Blackwell Scientific Publications 32 Jacob, C.O., van der Meide, P.H. and McDevitt, H.O. (1987)J. Exp. Med. 166, 798-803 33 Debray-Sachs, M. et al. (1991)J. Autoimmunity 4, 237-248 34 Campbell, I.L., Kay, T.W.H., Oxbrow, L. and Harrison, L.C. (1991)J. Clin. Invest. 87, 739-742 35 Jacob, C.O., Aiso, S., Michie, S.A., McDevitt, H.O. and Acha-Orbea, H. (1992) Immunology 87, 968-972 36 Bach, J.F. Ann. N. Y. Acad. Sci. (in press)
D.onor cell chimerism permitted by mmunosuppressive drugs: a new view of organ transplantation Thomas E. Starzl, Anthony J. Demetris, Noriko Murase, Angus W. Thomson, Massimo Trucco and Camillo Ricordi One line of thought in organ transplantation feels that immunosuppressive drugs can lead to tolerance induction by allowing a previously unrecognized common mechanism of cell migration and microcbimerism to occur, persist, and in some cases, become drug independent. It has been recognized that there is a spectrum of susceptibility of different organs to cellular rejection and that the variable ability of these organs to induce donorspecific nonreactivity reflects their comparative content of migratory leukocytes. Here, Thomas Starzl and colleagues discuss bow many of the enigmas of transplantation immunology can be explained by this cbimerism. The prevention of organ rejection by various immunosuppressive agents has been described increasingly in terms of tbe molecular site of disruption of the alloactivated T-cell response ~,2. Recent evidence, however, suggests that the control of rejection and, ultimately, graft acceptance depend on a permissive effect of these drugs on a mutual host--graft leukocyte rn;granon that leads in successful cases to mixed, long-term microchimerism in the recipient as well as the transplant 3(Fig. 1). An empiric drug regimen Observations compatible with this concept were reported in 1963 when combination therapy with azathioprine and prednisone was introduced for kidney transplantation 4. There is a characteristic cycle of renal graft rejection in the first few days or weeks that can be reversed with steroids. The ability to reduce (Fig. 2), or sometimes even to stop, treatment was thereafter
confirmed in cases of transplantation of the liver, heart and other organs. The reproducibility of these events led to the fundamental therapeutic dogma that forms the basis of whole organ transplantation surgery. It calls for daily baseline treatment with a maintenance drug or drugs (originally azathioprine) plus trial and error intervention with the highly dose-manouverable adrenal cortical steroids, along with anti-lymphoid agents to whatever level is required to maintain stable graft function. Throughout the years, this policy framework has accommodated increasingly potent new agents with variable sites of action (Table 1). The chimeric host and graft Under the regimes described above it became evident that something, not drug specific, appeared to have changed in either the graft, the recipient or both. But what?
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Vol. 14 No. 6 1993