IDDM: long honeymoon, sweet ending

3

Feinberg WM, Seeger JF, Carmody RF, Anderson DC, Hart RG, Pearce LA. Epidemiologic features of asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation. Arch Intern Med 1990;

150: 2340-44. Petersen P, Boysen G, Godtfredsen J, Andersen E, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989; i: 175-79. 5 Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circulation 1991; 84: 527-39. 6 The Boston Area Anticoagulation Trial of Atrial Fibrillation Investigators: the effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11. 7 Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. JACC 1991; 18: 349-55. 8 Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992; 327: 406-12. 9 Stroke Prevention in Atrial Fibrillation Investigators. Predicting thromboembolism in atrial fibrillation, I: clinical features of patients at risk. Ann Intern Med 1992; 116: 1-5. 10 Stroke Prevention in Atrial Fibrillation Investigators. Prediction of thromboembolism in atrial fibrillation, II: echocardiographic features of patients at risk. Ann Intern Med 1992; 116: 6-12. 11 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: 1255-62. 4

IDDM:

long honeymoon,

sweet

ending

See pages 704, 706

By any criterion, insulin-dependent diabetes mellitus (IDDM) is a disease that deserves a cure. Two reports in this issue show that we may be closing in on this particularly elusive goal. Both research groups have investigated the non-obese diabetic (NOD) mouse, which is a reasonably faithful model of the human disease.’ IDDM in both species is characterised by "insulitis"-ie, infiltration of the pancreatic islets by immune cells that selectively pick off the (3 cells. Insulitis affects virtually all NOD mice by a few weeks of age; in over 80% of female mice but in only 20% of males, the condition progresses within 3-10 months to clinical diabetes, which is fatal without insulin treatment. During the prediabetic phase, insulitis gathers momentum but has not yet destroyed a critical mass of (3 cells. The long duration of this period is an invitation to try to arrest the autoimmune damage and so prevent diabetes. Various approaches have been attempted. Blanket immunosuppression with non-selective drugs such as cyclosporin, given to NOD mice early in the prediabetic phase, can profoundly reduce the proportion of animals that subsequently manifest diabetes.2 Curiously, non-specific stimulation of the immune system in prediabetic NOD mice, by use of BCG or complete Freund’s adjuvant, also decreases the incidence of diabetes.’°4 A more precise strategy is to target the autoimmune responses provoked by specific as such the enzyme glutamic acid (3-cell autoantigens or shock heat decarboxylase (GAD), protein 60 (hsp60), which is co-expressed with insulin in the (3-cell secretory granules.5,6 Diabetes can be prevented by induction of immune tolerance to GAD in prediabetic mice.5 In newly diagnosed patients with IDDM, immunomodulatory drugs such as cyclosporin can induce remissions lasting several months.’ The latest reports each break new ground in several ways. Elias and Cohen gave a synthetic peptide (p277), which is part of the hsp60 molecule, to NOD mice aged

684

v

G

-f

v

Figure: Remission rates in newly diagnosed IDDM patients reported by Shehadeh et al after treatment with (8) or without (D) a single injection of BCG, and by the Canadian-European Study Group during treatment with (8) or without (0) cyclosporin7 12-17 weeks. p277 administered to prediabetic (12-week) mice virtually prevented diabetes. Even more excitingly, the peptide greatly reduced the frequency of fatal hyperglycaemia among mice treated at 15-17 weeks,

when many were already mildly hyperglycaemic; some animals became normoglycaemic. p277 substantially decreased the proportion of islets affected by insulitis, apparently by raising a population of anti-idiotypic T lymphocytes that inhibited the effector T cells which recognise the offending portion of hsp60 and are responsible for destroying the p cells.8 By contrast, Shehadeh et al gave BCG or complete Freund’s adjuvant late in the prediabetic phase (11 weeks), just before the earliest expected onset of diabetes. Both agents reduced the frequency of diabetes at 24 weeks, from 75% to 5%. Although the immune response was evidently channelled away from 0-cell destruction, neither BCG nor Freund’s adjuvant had any obvious impact on the histological appearances of insulitis. Both studies are novel in that the treatments were given relatively late in the natural history of the disease, and p277 stands out by being effective in some cases after the onset of diabetes. There are obviously wide species and credibility gaps between mouse and man. Shehadeh et al

bridge these by undertaking a preliminary clinical trial of BCG in patients with IDDM. BCG was given once within a month of diagnosis, with initially spectacular results: 1 and 3 months later, 35% and 65% of BCG-treated patients were in remission vs 3-5% and 7% of untreated controls at those times. Thus, one BCG injection apparently increases ten-fold the remission rate among recently diagnosed IDDM patients. However, we set out to

remember that as many as 40% of all IDDM patients enjoy a remission of some degree after starting insulin treatment. During this so-called honeymoon period, insulin doses can often be greatly reduced or even withdrawn completely.9 Remission is due to partial functional recovery of the surviving 0 cells, whose capacity to secrete insulin is impaired by hyperglycaemia itself." The honeymoon often lasts 3-6 months but may continue for 2 years; it ends when the remaining 0 cells are finally destroyed by the continuing autoimmune need

to

onslaught.

The ability of insulin alone to induce lengthy remissions can make it difficult to identify any specific effects of additional treatments that aim to modify the underlying autoimmune process. The figure shows the remission rates reported by Shehadeh et al set in the context of data from the Canadian-European Diabetes Study Group/ in which newly diagnosed IDDM patients were treated randomly with cyclosporin or placebo. Several points deserve comment. First, although BCG treatment apparently achieved a substantially higher remission rate than cyclosporin, this difference is partly due to the stricter criteria for remission in the Canadian-European study. Moreover, the profound effect of BCG is amplified by the unusually low remission rate among those who were not given BCG; the higher rate among the controls in the Canadian-European study is more typical of the normal honeymoon.9 This discrepancy may relate to Shehadeh’s use of historical controls, whose basic diabetic management may have differed in some way from the subjects who received BCG. Nonetheless, Shehadeh et al have made a major advance by inducing high remission rates with a single innocuous injection, whereas had to be cyclosporin given continuously and caused significant side-effects including renal impairment.’ Overall, both reports raise hopes that we shall soon be able to extend the honeymoon period in human IDDM. This does not yet amount to a cure, since most of these remissions have lasted only a few months. are more likely to succeed if Immunomodulatory agents rises on diabetes, but it before the final curtain given long is still impossible to identify for certain which subjects at high risk of IDDM will actually go on to develop the disease." When promising drugs are identified, large and rigorous clinical trials will be needed to determine whether the life sentence of IDDM can be quashed, commuted, or merely deferred. In the case of something as simple and apparently harmless as BCG, these trials should be undertaken without delay. Gareth Williams Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool, UK 1 Castano L, Eisenbarth GS. Type 1 diabetes: a chronic autoimmune disease of human, mouse and rat. Annu Rev Immunol 1990; 8: 647-79. 2 Tochino Y. The NOD mouse as a model of type 1 diabetes. CRC Grit Rev Immunol 1987; 8: 49-81. 3 Guytingco R, Quddus J, Richardson B, Pek SB. Single administration of Bacillus Calmette-Guérin (BCG) vaccine in nonobese diabetic (NOD) mice results in suppression of in vitro T lymphocyte proliferation and regression of insulitis. Diabetes 1991; 40 (suppl 1): 152A. 4 McInerney MF, Pek SB, Thomas DW. Prevention of insulitis and diabetes onset by treatment with complete Freund’s adjuvant in NOD mice. Diabetes 1991; 40: 715-25. 5 Tisch R, Yang XD, Singer SM, Liblav RS, Fuggar L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993; 366: 72-75. 6 Brudzynski K, Martinez V, Gupta RS. Immunocytochemical localization of heat-shock protein 60-related protein in beta-cell secretory granules and its altered distribution in non-obese diabetic mice. Diabetologia 1992; 35: 316-24. 7 Canadian-European Diabetes Study Group. Cyclosporin-induced remission of IDDM after early intervention: association of 1 year of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988; 37: 1574-82. 8 Elias D, Reshef T, Birk OS, van der Zee R, Walker MD, Cohen IR. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65 kDa heat shock protein. Proc Natl Acad Sci USA

1991; 88: 3088-91.

9

Koivisto VA, Aro A, Cantell K. Remissions in newly-diagnosed type 1 (insulin -dependent) diabetic patients: influence of interferon as an adjunct to insulin therapy. Diabetologia 1984; 27: 193-97. 10 Yki-Järvinen H. Glucose toxicity. Endocr Rev 1992; 13: 415—31. 11 Bingley PJ, Bonifacio E, Gale EAM. Can we really predict IDDM? Diabetes 1993; 42: 213-20.

Diagnostic diseases:

a

sexually transmitted challenge

tests for

Can you think of a way to develop a new generation of simple and inexpensive diagnostic tests for chlamydia and gonorrhoea? If so, we at the Rockefeller Foundation would like to hear from you. The Foundation lately launched the STD Diagnostics Challenge; the reward is the Rockefeller Foundation Science for Development Prize, which comes with a$1 million cash award (see p

726).

Why is the Foundation offering a prize? For centuries, prizes have had an important role in stimulating Harrison’s breakthrough innovations, from John development of the first accurate seafaring clock in 1762 (Board of Longitude prize) to Charles Lindbergh’s solo flight across the Atlantic in 1927 (Orteig prize). Compared with standard grant schemes, the prizechallenge mechanism encourages innovation by framing important problems and providing an incentive for their solution.

Why has the Foundation chosen to concentrate on diagnostics? There are more than 250 million new sexually transmitted infections world wide each year, and developing countries bear much of this burden. Chlamydia and gonorrhoea, the most common treatable bacterial infections, are responsible for over 75 million of STD

of the disease burden. Untreated and often irreversible complications, they especially in women, and sometimes results in death. Women are more likely to acquire STD infections than men because of the greater efficiency of male to female transmission. In addition, men and women with these infections are three to five times more likely to acquire and transmit human immunodeficiency virus. Treatment for these infections is inexpensive (US$1-3) and readily available; diagnosis is not. Without pointed measures this situation is unlikely to change because there is little market incentive for the diagnostics industry to develop tests appropriate for countries with few resources to pay for them. The use of diagnostic tests is crucial for detection and control of these diseases. Symptoms of different STDs may be similar and dual infection is common. Furthermore, whereas men develop painful symptoms, most STD infections in women are virtually symptomless; a woman may therefore be unaware of her condition. Existing diagnostic methods are unsuited to field conditions: they are expensive (US$5-12), require electricity, are difficult to interpret, and are slow. Moreover, specimens for these tests necessitate pelvic examination, which in itself requires a sterile speculum and electricity for good lighting. A new generation of tests is urgently required. The tests must be capable of diagnosing symptomless infection, as well as inexpensive, simple, hardy, rapid, and accurate; and they should not depend on invasive procedures to obtain samples. We at the Foundation hope that our challenge will

these

cases

and for

cause

severe

most

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