Immunointervention in autoimmune diseasesfrom cellular selectivity to autoantigen specificity

Journal of Autoimmunity (1992) 5 (Supplement A), 3-10

I m m u n o i n t e r v e n t i o n in A u t o i m m u n e Diseases F r o m Cellular Selectivity to Autoantigen Specificity

Jean-Francois

Bach

Immunology Department, H6pital Necker, Paris, France I m m u n o s u p p r e s s i v e a g e n t s h a v e p r o v e d to be r e m a r k a b l y s u c c e s s f u l in c o n t r o l l i n g the c o u r s e o f a g r o w i n g n u m b e r o f a u t o i m m u n e diseases. T h e usual o c c u r r e n c e o f r e l a p s e s w h e n the t r e a t m e n t is s t o p p e d a n d the p e r s i s t ing r i s k o f l o n g t e r m c o m p l i c a t i o n s l i n k e d to o v e r - i m m u n o s u p p r e s s i o n h a v e p r o m p t the s e a r c h for n e w a p p r o a c h e s , a i m i n g at m o r e r a p i d and s e l e c t i v e i n t e v e n t i o n and e a r l i e r o n s e t o f t h e r a p y . N e w c h e m i c a l s and m o n o c l o n a l a n t i b o d i e s p r e s e n t l y r e p r e s e n t the m a i n clinical o r i e n t a t i o n s , w h i l e at the e x p e r i m e n t a l level m a j o r efforts a r e d i r e c t e d t o w a r d s p e p t i d e t h e r a p y ( a u t o a n t i g e n , T cell r e c e p t o r ) a n d t o l e r a n c e i n d u c t i o n .

Introduction

At present, immunointervention in a u t o i m m u n e disease ( A I D ) is essentially confined to chemical immunosuppression. T h e introduction of cyclosporin has led to a remarkable extension of the clinical applications of immunosuppression, involving new diseases in which there was not, until recently, even the hint of an a u t o i m m u n e origin. Problems persist, however, which p r o m p t clinicians and immunologists to search for new strategies that will permit these limitations to be overcome. It is the aim of this article to review the achievements and limitations of chemical i m m u n o suppressants and to discuss, in a realistic way, the new strategies under study. A series of remarkable

successes

It is fair to say that despite persisting problems, m o d e r n immunosuppressive drugs, and cyclosporin in particular, have brought a major revolution in the treatment of a u t o i m m u n e diseases. T h e most conspicuous effect is the clearcut and often spectacular clinical improvem e n t obtained in a wide spectrum of a u t o i m m u n e diseases (Table 1). T h e effect is often rapid and virtually complete. Interestingly, clinical efficacy is not always 3 0896-8411/92/0A0003 + 08 $03.00/0

© 1992 Academic Press Limited

4

Jean-Francois Bach T a b l e 1. Expansion of the clinical use of immunosuppression in autoimmune disease

Established indications Nephrotic syndrome Rheumatoid arthritis SLE Uveitis

New indications Primary biliary cirrhosis Psoriasis

Putative indications Altergic asthma Aplastic anemia Atopic dermatitis Crohn's disease Graves' disease Lichen planus Multiple sclerosis Type I diabetes

associated with a parallel effect on biological parameters supposed to represent pathogenic markers of the disease. T h u s cyclosporin improves the clinical condition of M R L mice [1] or lupus patients [2] without necessarily decreasing a n t i - D N A antibody production. Cyclosporin efficacy is more clear in diseases in which the pathogenic role of T cells is prominent, but interesting data have also been obtained in supposedly antibody-mediated diseases such as systemic lupus erythematosus, myasthenia gravis, allergic asthma and pemphigus. T h e question remains as to the drug's m o d e of action in this setting (helper T cells? inflammatory cells?...). In some diseases, such as nephrotic syndrome or psoriasis, the cyclosporin target cell is ill-defined and is not necessarily a T cell, although this is still the more likely hypothesis, whatever the m o d e of T cell involvement in these diseases. T h e recent observation that an a n t i - C D 4 monoclonal antibody improved the case of a patient with psoriasis [3] supports this assumption. Cyclosporin-induced nephrotoxicity is often considered to be a serious side effect of the drug, which hampers its usage in A I D where toxicity is more difficult to accept than in organ transplantation. T h e risk ofnephrotoxicity is a real one and represents a major concern when irreversible renal interstitial fibrosis occurs. It has been our experience, however, that nephrotoxicity remains minimal when patients are submitted to careful and regular monitoring both by creatininemia and drug blood level follow-up. It is reassuring to note that none of m o r e than 400 diabetic patients who have received cyclosporin for periods of up to 2 years with doses ranging from 5 to 7.5 mg/kg/day show detectable renal failure 6 months after cessation of the drug administration. Some centers which have not used these moderate dosages with precise monitoring have been less fortunate which has led to concern in some clinical circles. W e believe that nephrotoxicity is not presently the major restriction to the development and extension of cyclosporin usage in A I D . Three orders of limitations T h e use of cyclosporin is associated with three types of difficulties which limit its wider application in A I D . First, not all patients respond to cyclosporin. T h i s is m o r e obvious in some diseases (e.g., type I diabetes or C r o h n ' s disease) than in others where most patients

Immunointervention in a u t o i m m u n e diseases

T a b l e 2.

5

Risk factors for immunosuppression-associated malignancies

1. T cell impact 2. Immunosuppression depth: high drug dosage and/or combination of several drugs 3. Long duration of treatment 4. Carcinogenic effect for certain drugs (alkylating agents) 5. Environmental factors (e.g., sun exposure, EBV or CMV preinfection) ~t do react favorably (e.g., psoriasis). T h e search for factors predictive of drug responsiveness do not appear to indicate that cyclosporin unresponsive patients represent a subset of patients with different underlying cellular mechanisms. It is m o r e likely that non-responsiveness is linked to insufficient drug dosage or too late initiation of the immunosuppressive therapy. It is generally difficult, often impossible, to increase the drug dosage and expose the patient to unacceptable side-effects (nephrotoxicity, infections and malignancies). Earlier intervention poses specific problems that will be discussed further. Second, relapses are frequently seen when the treatment is withdrawn indicating that, as in organ transplantation, the drug has not induced antigen-specific tolerance. T h i s is a c o m m o n feature of immunosuppressive treatments in chronic diseases where the etiological factors persist. Even in such settings, however, the disease often evolves by phases of exacerbations and remissions and one may hope in individual cases that the exacerbation which justified the drug administration will have ceased at the end of the treatment [4]. T h e p r o b l e m is worsened in some diseases such as type I diabetes by the occurrence of relapses under continuous cyclosporine treatment. T h e s e relapses are apparently linked to the autonomous organ destruction of the limited amount of persisting tissue that takes place even though the a u t o i m m u n e process has been stopped. T h i s destruction is linked, in the case of diabetes, to the toxic effect of the transient hyperglycemic episodes that persist in these patients in spite of their remission from insulin dependency. Third, even if no opportunistic infection is seen and exceptional cases of lymphoma have been observed so far, the risk of chronic overimmunosuppression is a constant fear when immunosuppressive agents are administered for long periods of time. T h e occurrence of malignancy depends on well-defined factors (Table 2). This risk obliges one to limit the duration of cyclosporine administration to a m a x i m u m of 2-3 years even though it is not that longer treatments with low dosages are really harmful. T h e analysis of data obtained in organ transplant patients being treated for several years with low dose cyclosporine is necessary before embarking on prolonged treatment in A I D . T h e s e three types of limitations pose the p r o b l e m of the risk~benefit ratio of i m m u n o s u p p r e s s i v e therapy in A I D . It is not easy to evaluate and compare realistically and objectively, disease and treatment risks (Table 3). T h e quality of life requested by patients should be taken in account despite physicians' reservations. However, the long t e r m side-effects should be given a high priority consideration. Search for increased cellular selectivity

Cyclosporine represents a major progress over azathioprine, cyclophosphamide and steroids in terms of cellular selectivity. T h e drug does not depress bone m a r r o w

6

Jean-Francois Bach Table 3. Risk~benefit ratio

Disease risks

Treatment risks

Reduced survival ex: MS

Direct toxicity ex: Cyclophosphamide sterility CsA nephrotoxicity OKT3 systemic reaction

Handicap Physical (ex: RA) Psychological (ex: skin diseases)

Overimmunosuppression Infections Malignancies

Constraints due to the disease or its treatment (ex: type I diabetes)

hemopoiesis and acts selectively on the production of well defined lymphokines after binding to a cytosol receptor (cyclophilin). It remains, however, as discussed above, that side effects occur and that the lymphokines in question are involved in a n u m b e r of immune reactions other than the targetted undesirable reaction. Progress could derive from the availability of chemicals with a higher therapeutic index. Several candidates are presently being clinically evaluated namely: cyclosporin analogues, F K 506, rapamycin, mycophenolic acid, deoxyspergualine, etc. It has not yet been determined whether these agents will show a similar (or improved) efficacy with fewer side-effects (particularly reduced nephrotoxicity). Randomized trials in progress with F K 506 will soon provide us with this information. It is apparent, however, that even in the best case, this approach will not generate a major improvement since it will not solve any of the three limitations discussed above. Other selective agents currently include monoclonal antibodies and immunotoxins. 'A n u m b e r of these biological agents have been used in experimental animals and in man (Table 4). T h e case of monoclonal antibodies is particularly interesting since most of them show full efficacy without any direct toxicity (with the exception of anti-CD3 antibody-induced cytokine release). A major problem is that of the xenosensitization induced by the murine protein, but this difficulty has now been circumvented by the successful use of humanized antibodies. Recent results obtained with a chimeric anti-CD7 antibody showing absence of anti-isotypic or idiotypic sensitization (our unpublished results) are very encouraging in this context.

Search for antigen specificity Ideally, one would like to intervene specifically in the pathogenic autoimmune reaction responsible for the disease onset or maintenance. This is still an impossible goal in most A I D since the target autoantigen is not yet known exactly. Recent results obtained in several laboratories using the model of experimental allergic encephalomyelitis (EAE) have resulted in optimism that this will be possible in the future. Indeed, it is possible to prevent the onset of EAE in mice by giving peptide analogues of the encephalitogenic peptides [5].

I m m u n o i n t e r v e n t i o n in a u t o i m m u n e diseases

7

T a b l e 4. Present and potential cellular targets for immuno-

intervention in autoimmune diseases

Cytokine production cyclosporin FK506 T cell receptor anti-a[3 mAb anti-CD3 mAb anti-V[3 mAb MHC antigens anti-class II mAb anti-y-IFN mAb Activation markers anti-IL-2R mAb IL-2 toxin Adhesins anti-CD4 mAb anti-LFA- 1 mAb anti-ICAM-1 mAb

Experimental animals

Patients

+ +

+ +

+ + +

+ + ND

+ +

ND ND

+ +

+ in progress

+ + +

+ + ND

ND: not done. mAb: monoclonal antibody.

Before having direct access to the autoantigen it is possible to act at the T cell receptor level on determinants that are related to antigen specificity: either the antigen binding site itself (idiotype) or the V[3 fragment used in the a u t o i m m u n e response in question (Table 5). Anti-idiotypic prevention of A I D has been attempted by means of T cell vaccination [6]. V[3 orientated therapy has been used successfully in E A E both with anti-V[3 monoclonal antibodies [7] and a n t i - T C R peptide sensitization [8]. It is not yet clear whether the approach is feasible in spontaneous A I D . Results obtained in various laboratories in diabetic N O D mice and in various h u m a n A I D remain contradictory and confusing. T h e hope remains, however, that V[3 gene usage is indeed restricted in some A I D . Results obtained in our laboratory by C. Carnaud support this theory by showing that diabetogenic T cells taken f r o m the spleen of diabetic N O D mice lose their capacity to transfer diabetes in irradiated recipients after depletion ofV[~ + T cells. It is hoped that as has been shown in transplantation models [9], a n t i - C D 4 antibodies will induce tolerance to autoantigens. Immediate action

Cyclosporin represents a remarkable prophylactic treatment of rejection. Like most other i m m u n o s u p p r e s s i v e agents, however, it loses its efficacy in acute rejection episodes where only high dose steroids, anti-thymocyte globulins and O K T 3 are active, suggesting the classification of immunosuppressive agents into three

8

Jean-Francois

Bach

Table

5. Therapeutic strategy in autoimmune diseases

Targets 1. Cellular activity

2.

Chemicals (cyclosporin analogues, FK506, rapamycin. . . . ) Monoclonal antibodies (TCR, CD3, CD4 . . . . ) Immunotoxins --antibody-toxin conjugates --IL-2-toxin conjugates

Antigen specificity

Timing 1. Immediate maximal efficacy

2. Early intervention in the natural history of the disease

Peptides of the autoantigen TCR idiotypes T cell vaccination V[3 fragments --anti-V~ antibodies --V~3 synthetic peptides Monoclonal antibodies - - T C R ~[3 --CD3, CD4 . . . . High dose corticosteroids Advantages --less organ deterioration --autoimmune response more sensitive to immunointervention Constraints --reliable predictive diagnosis --minor toxicity

T a b l e 6. Three levels of immunointervention

Prophylaxis (chronic treatment) Hyperacute immune reaction (short term treatment) Antigen specific tolerance (treatment of limited duration)

CsA FK506 Low dose steroids

OKT3 High dose steroids

Anti-CD4 mAb

+

+

+

-

+

+

categories according to their capacity to prevent or cure rejection or induce tolerance (Table 6). T h e same approach should be used in A I D where acute exacerbations should be initially treated with drugs of the second type (e.g., O K T 3 ) followed by administration of drugs of the first type (e.g., cyclosporin) which unlike agents of

Immunointervention in a u t o i m m u n e diseases

Genetic

markers

~ J .8_

~

HLA nm-HLA

9

Families

Earlydetection of the J autoimmune reaction ~ ""

~ ,, /cells ~-Organ degradation ]

L~eneral population

~ - - Lowdoseisup immunosuppressants "~en modifiers

~ ~

Rapidand complete intervention

~

elective

and possiblyspecific therapy

Time Figure 1. Therapeutic strategy in type I diabetes according to the different stages of the disease.

the second category can be administered safely for long periods of time. T h i s has been demonstrated in the case of N O D mice which show quasi-immediate regression of insulitis and hyperglycemia when given an a n t i - T cell receptor monoclonal antibody [10]. Towards early intervention

A last approach relates to early administration of immunosuppressive therapy in the natural history of the disease. T h i s requires early diagnosis of the disease or better recognition of the predisease state by adequate genetic and immunological markers as routinely p e r f o r m e d in type I diabetes [11]. T h i s approach has the double advantage of intervening at a stage when most of the target tissue is still present and of attacking a less intense and consequently more sensitive i m m u n e response. Several lines of evidence indicate that the a u t o i m m u n e reactions responsible for A I D are sensitive to a wider range of immunosuppressive agents at early stages of the disease than at late stages. T h u s , in N O D mice m a n y agents are prophylactically efficient early in the disease (e.g., I L - 1 , T N F , Poly I-C). Cyclosporin remains efficacious for m a n y months but finally loses its effect at the m o s t advanced stages when only monoclonal a n t i - C D 4 or a n t i - T C R antibodies remain effective [10, 12]. T h i s approach is probably of use in m a n y A I D and is m a n d a t o r y in some diseases such as type I diabetes in which the clinical diagnosis is made late in the natural history of the disease. However, it requires reliable prediction tests and non-toxic immunointervention methods, the only one to be acceptable in such patients with minor disease manifestations. Conclusions

I m m u n o s u p p r e s s i v e agents have already accomplished a major advance by changing the face of a n u m b e r of diseases for which no alternative treatment was available. M o r e

10

Jean-Francois Bach

progress remains to be made in several directions, after which it may reasonably be hoped that combination of early diagnostic tests (genetic and immunological), efficacious initial immunosuppressive attack using chemicals and monoclonal antibodies with low toxicity will prepare the initiation of autoantigen specific peptides (Figure 1) making the immunoprevention of major A I D possible in the long term.

References 1. Mountz, J. D., H. R. Smith, R. L. Wilder, J. P. Reeves, and A. D. Steinberg. 1987. CS-A therapy in MRL lpr/lpr mice: amelioration of immunopathology despite autoantibody production.ft. Immunol. 138:157-163 2. Feutren, G., S. Qu6rin, L. H. No61, L. Chatenoud, G. Beaurain, F. Tron, P. Lesavre, and J. F. Bach. 1987. The effects of cyclosporin in severe systemic lupus. J. Pediatrics 111: 1063-1068 3. Nicolas, J. F., N. Chamchik, J. Thivolet, J. Wijdenes, P. Morel, and J. P. Revillard. 1991. CD4 antibody treatment of severe psoriasis. Lancet 338" 321 4. Wraith, D. C., D. E. Smilek, D. J. Mitchell, L. Steinman, and H. O. McDevitt. 1989. Antigen recognition in autoimmune encephalomyelitis and the potential for peptidemediated immunotherapy. Cell 59:247-255 5. Lider, O., T. Reshef, E. Beraud, A. Ben Nun, and I. R. Cohen. 1988. Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 239" 181-183 6. Acha-Orbea, H., D. J. Mitchell, L. Timmermann, D. C. Wraith, G. S. Tausch, M. K. Waldor, S. S. Zamvil, H. O. McDevitt, and L. Steinman. 1988. Limited heterogeneity of T cell receptors from T lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54:263-273 7. Urban, J. L., V. Kumar, D. H. Kono, C. Gomerz, S. J. Horvath, J. Clayton, D. G. Ando, E. E. Sercarz, and L. Hood. 1988. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell 54:577-592 8. Vanderbark, A. A., G. Hashim, and H. Offner. 1989. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341:541-544 9. Cobbold, S. P., S. Qin, and H. Waldmann. 1990. Reprogramming the immune system for tolerance with monoclonal antibodies. Immunology 2" in press 10. Semp6, P., P. B6dossa, M. F. Richard, M. C. Villa, J. F. Bach, and C. Boitard. 1991. Anti-a/J3 T receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice. Fur. ft. lmmunol. 21:1163-1169 11. Irvine, W. ]'., C. M. McCallum, R. S. Gray, C. J. Campbell, L. J. P. Duncan, J. Farguhan, H. Vaughan, and P. J. Morris. 1977. Pancreatic islet-cell antibodies in diabetes mellitus correlated with the duration and type of diabetes, coexistent autoimmune disease and HLA type. Diabetes 26:138-147 12. Shizuru, J. A., C. Taylor Edwards, B. A. Banks, A. K. Gregory, and C. G. Fathman. 1988. Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T helper lymphocytes. Science 240:659-662