**5. Vaccines against infections**

and facilitate treatment. Patients with residual insulin secretion usually get lower HbA1c, and residual insulin secretion facilitates the treatment, decreases the risk for serious hypoglycaemia and the risk of keto-acidosis [10]. Already very modest beta cell function, with peak stimulated C-peptide above 0.2 nmol/L seems to reduce long-term complications [11]. Furthermore, Cpeptide per se has been proposed to decrease the risk of complications, especially neuropathy. There is increasing evidence that C-peptide is not just a connecting peptide to keep the two insulin chains in in a certain structure, but a hormone with several important effects [12]. The relevance of saving beta cells and improving their function has become even more evident when studies suggest that beta cells may regenerate [13, 14]. If this is the case an end of the

The generally accepted opinion is that the majority of the pancreatic beta cells are lost at the diagnosis of Type 1 diabetes. The beta cells are supposed to be killed by an autoimmune process precipitated and promoted by genetic and environmental factors. In recent years the dogma saying that most beta cells are dead has been questioned, and regeneration of the beta cells seems not only possible but quite plausible. Actually that was discussed as a possibility already several decades ago( Fig 1). Thus, many beta cells may still be living in pancreas although they do not respond normally to stimulus with insulin secretion. Auto-antibodies are usually found, but regarded as markers of the process, rather than causing beta cell death. The auto-antibodies react against the islet cells (Islet Cell Antibodies; ICA) [16] or against specific auto-antigens such as Insulin Auto-antibodies against Insulin (IAA) [17], against Glutamic Acid Decarbox‐ ylase (GADA) [18], against Tyrosin Phosphatase ( IA-2A) [19] or against ZincTransport Anti‐ gen (ZnTA) [20]. These antigens are attacked by the own immune system. Dysregulation of the immune system is thought to allow a self-destructive process. Mononuclear cells, mainly

Several immune interventions have been tried since the 1970ies we tried plasmapheresis in Linköping, Sweden, with the aim to preserve residual beta cell function, but so far all different approaches have shown insufficient efficacy and/or given unacceptable adverse effects [21-28]. Broad immunosuppressive or immunoblocking therapies with steroids, cytostatics, high doses of immunoglubulins, anti-lymphocyte globulins have shown some but unfortunately limited efficacy, and adverse events have lead to restrictions both in dose and time. Our studies using photopheresis did show some efficacy, and although the treatment was very laborious it has regained some interest. However, most encouraging is the use of monocloncal antibodies, especially against CD-3 [29-31] but also against CD-20 [32]. Unfortunately treatment with monoclonal antibodies in doses large enough to give efficacy also cause rather common and occasionally serious adverse events.Therefore such therapies are rarely justified as preventive

T-cells, seem to play the most important role for the killing of the beta cells.

destructive process might lead to cure of T1D [15].

494 Type 1 Diabetes

**3. The immunological disease process**

**4. Immune interventions**

Traditional vaccinations could either contribute to the development of T1D, or T1D could be prevented by vaccination. Already in the 1920ies mumps infection was shown to be a possible cause of insulin dependet diabetes [35]. A general vaccination against mumps might then either decrease the incidence of T1D, or vaccination with living virus might on the contrary initiate an autoimmune process leading to an increased incidence of T1D. None of these asso‐ ciations have been proven [36, 37]. Neither have there been any associations between vacci‐ nations against other microbes and the development of diabetes [38]

placebo than in the DiaPep277 group. There were no o adverse events. The treatment of newly diagnosed T1D adults with DiaPep277 seemed to preserve residual insulin secretion through induction of a shift from Thr-1 to Thr-2 cytokines. However, the efficacy seen in adults could not be confirmed in children and adolescents with T1D [50,51] in spite of interesting immu‐ nologcval results [52]. In a recent Phase III trial no immunological difference could be found between adults treated with Diapep 277 or those treated with placebo [53]. Treatment with Diapep 277 seemed to preserve C.peptide but only C-peptide after Glucagon stimulation, but not after Mixed Meal Tolerance Test [54]. Thus it is still unclear whether Diapep 277 has a place

Immune Intervention in Type I Diabetes Mellitus

http://dx.doi.org/10.5772/52801

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Traditional vaccination is strengthening the immune reaction against an antigen, usually an infectious microbe. Methods of reducing a pathological specific immune response eg in auto‐ immune diseases like T1D can be regarded as a sort of "inverse" vaccination. In allergy toler‐ ance against the allergens is created by presenting the antigen/allergen/s in gradually increasing doses. Such Immunotherapy has become quite efficacious [55] and the adverse

It would be reasonable to try to reduce an autoimmune process in an analogue way, by ad‐ ministration of auto-antigen/s. Thus, instead of suppressing the immune system, the immune response should be modulated by presenting antigen/s in a way that the immune system shifts

If self-reactive T-cells directed against auto-antigens cause some cases of Type 1 diabetes a major question is why such self-reactive T-cells occur. Two mechanisms seem to be necessary for self-tolerance: Clonal deletion of self-reactive T-cells issued from the random recombina‐ tion of genes (negative selection), and generation of self-antigen-specific natural regulatory Tcells (Tregs) which can inactivate self-reactive T-cells in the periphery when they have escaped intra-thymic negative selection [57]. In T1D auto-reactivity against insulin is a common and early phenomenon. The important role of thymic insulin for development of self-tolerance has been demonstrated in transgenic mice [58], but there is still no technique to use this knowledge

Proinsulin and insulin and its different chains are so far the only known auto-antigens that are specific for the beta cells. Insulin has been used in trials to prevent diabetes among first degree relatives with increased risk of T1D. In Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) human ultralente insulin of 0.25 units x kg/day, or placebo, was given to subjects with >50%

or not as future intervention to preserve residual insulin secretion in adults.

**8. "Inverse vaccination "to reduce the immune response**

events are rare.

in clinical practice.

**9. Auto-antigen treatment**

**9.1. "Vaccination" with insulin**

from a destructive process to tolerance [56].

Entero virus infections are most suspected to cause T1D. Epidemiological studies have pro‐ vided evidence of coxsackie virus (CVB) infections in subjects who later develop T1D [39]. A CVBB4 strain E2 was isolated from pancreas of a diabetic child, and the virus was then passed into islet cells and found to cause diabetes in mice, which was taken as a proof of the concept that coxsackievirus can cause T1D [40]. So far vaccination against these types of infections to preserve beta cells has been disappointing,

The hygiene hypothesis suggests that the immune system would deviate less often towards an autoimmune process if the immune system was occupied by an ongoing defence against serious enemies. In accordance with this hypothesis, Calmette vaccination has been tried to preserve beta cell function but no clinical effect has been seen [41].
