Treatment of Presymptomatic (Stage 1) Type 1 Diabetes Pediatric Patients With Treg Cell Preparations and Anti-CD20 Antibody

Inclusion Criteria:

1. Age 6-16

2. 25 ≤ BMI ≤ 75 percentile (acc. to OLAF) with a lower weight threshold of 20 kg

3. Venous plasma glucose levels < 100mg% at fasting (70 to 100 mg/dl) and normalglucose tolerance test (at 120 minutes glycaemia <140 mg/dl) (acc. to PTD)

4. Insulin independence

5. C-peptide levels ≥ 1.0 ng/ml (central laboratory limit of normal) in fasting andpost-stimulation tests increase ≥ 100%

6. Participant has not yet been diagnosed with stage 2 or 3 type 1 diabetes mellitus (no history of dysglycemia, no history of clinical symptoms of type 1 diabetesmellitus)

7. HbA1c level (%) <5,7% (acc. to ADA)

8. Positive autoantibody titres (ICA, IAA, GAD, IA-2/ICA512, ZnT8) - low titers of twoor more antibodies (2-4 times the normal*); if high titer of one of the antibodies (≥ 4 times the norm, not applicable to ICA) re-screening allowed (the participantcan be included in the trial only after confirming two or more antibodies)

9. Ability to give informed consent by the child's legal representatives (and the childhimself or herself if he or she is over the age of 13 at the time of the trial [according to local law])

10. Ability of the child's legal representatives to manage diabetes, defined as bloodglucose levels control at least three times a day and the ability to dose insulincorrectly.

11. Venous access to guarantee blood donation

Exclusion Criteria:

12. Refusal to participate in the trial or lack of a signed informed consent form

13. Suspicion or diagnosis for a type of diabetes other than type 1 diabetes mellitus

14. Age under 6 or above 16

15. IgA deficiency or history of other diagnosed immunodeficiency (max. 7infections/year allowed, and the prognosis should indicate that the patient willremain in the study throughout its duration)

16. C-peptide levels < 1.0 ng/ml fasting and in post-stimulation tests increase < 100%

17. Glucose levels in venous blood ≥ 100mg% fasting

18. Glucose levels in venous blood after 1 and 2 hours in OGTT ≥ 200mg%

19. Glycated hemoglobin level (HbA1c) in venous blood ≥ 5,7%

20. BMI < 25 or > 75th percentile for a given age or weight of less than 20 kg

21. History of hypersensitivity to anti-CD20 or other components of the preparation

22. History of hypersensitivity to penicillin and/or streptomycin

23. Past or active infection with HBV, HCV, HIV, HTLV I/II, mycobacterium tuberculosis,syphilis. Laboratory evidence of infection without the need for clinical signs andsymptoms is sufficient for diagnosis.

24. Active infection with the EBV or CMV virus (positive IgM)

25. Any fungal, parasitic, viral, or bacterial infection

26. History of past or active cancer

27. Anemia, lymphopenia, neutropenia, or thrombocytopenia defined as a blood cell countbelow the lower limit of normal for age found within the last 6 weeks prior to trialinclusion

28. Elevated thrombotic activity/history of thrombosis episode

29. Any disease prior to inclusion in the trial currently requiring medication for morethan 3 months in history

30. Diagnosed autoimmune disease other than type 1 diabetes mellitus, including ahistory of Hashimoto's disease and coeliac disease

31. Taking anti-diabetic medication (including insulin) in the last 4 weeks prior totrial inclusion

32. History of retinopathy

33. History of hypertension

34. Current or history of albuminuria

35. For women in childbearing potential/menstruating women: pregnancy (from medicalinterview) or unwillingness to exercise sexual restraint or use effective forms ofcontraception for the duration of the trial and up to 4 months after completion, ifapplicable. The following contraceptive methods are acceptable: bilateral fallopian tubeclosure, sterilization in men, appropriate use of hormonal contraception thatinhibits ovulation, hormone-releasing IUDs, and copper IUDs, male or female condomswith spermicide; and cap, uterine disc, or sponge with spermicide.

36. Breastfeeding

37. For males over 15 years of age: expressed intention to have offspring or donatesperm during the trial or within 4 months after the end of the trial, if applicable

38. Excessive anxiety of the participant or his/her legal representatives regarding theprocedures used in the trial

39. Any medical problem that, in the opinion of the investigator, may adversely affectthe participant's health if included in the trial

40. Legal representatives and/or children over the age of 15 with an identified alcoholand/or psychoactive substance addiction

41. History of disease of unknown etiology

42. History of Creutzfeldt-Jacob disease

43. History of progressive dementia or degenerative neurological disease, including ofunknown origin

44. History of taking hormones derived from the human pituitary gland (e.g., growthhormone)

45. Treatment with immunosuppressants

46. History of corneal, scleral, and dural transplant or undocumented neurosurgery

47. History of occurrence of risk factors related to the participant's travel, wherethere is a possibility of exposure to regional infectious diseases

48. Physical signs that indicate the risk of an infectious disease

49. History of xenogeneic transplant