ABSTRACT

This PhD dissertation has been based on studies performed at Hagedorn Research Institute, Gentofte. The purpose has been to explore the capability of regulatory T cells in preventing transfer-induced autoimmune diabetes in co-transfer models.

Organ specific autoimmunity is prevented by several mechanisms; the majority of autoreactive T cells are deleted in the thymus, however, the ones that escape from the thymus are deleted, energized or under suppression of regulatory T cells in the periphery.

Regulatory T cells were studied in transfer models where they were co-transferred with diabetes inducing cells isolated from induced acutely diabetic rats. Transfer of diabetogenic T cells alone resulted in a high diabetes incidence within a short time interval in the recipients. Co-transfer of unfractionated leukocytes from healthy adult rats was able to prevent diabetes development. Full protection was achieved when the protective cells were transferred 3-4 days before the autoreactive, while the protection only was partial when protective cells were transferred only two days before. Protection resided in the CD4 + fraction as purified CD4 + T cells prevented both transfer-induced as well as spontaneous diabetes. When the CD25 + cells were depleted from these before transfer, the ability to prevent diabetes was significantly impaired. By contrast, transfer of a low number of CD4 + CD25 + T cells was able to prevent diabetes development confirming their regulatory potential.

The ability of a small subset of leukocytes to protect from an accelerated form of diabetes gives hope for a cure of human diabetes with regulatory T cells. Regulatory T cell therapy could be translated into humans by generation/expansion of this specialized subset in vitro. Or alternatively regulatory T cells could be induced in situ via administration of autoantigens in a tolerogenic way.