Transplantation of organ cultured foetal islets of Langerhans in mice
thesisposted on 15.12.2014, 10:30 by Maria. Koulmanda
Foetal islets are functionally immature but retain their capacity for proliferation if harvested and cultured in an appropriate manner. Graft function was shown to depend largely on the gestational age and conditions of organ culture prior to transplantation. The required period of organ culture for optimal graft function was investigated for foetal mouse pancreas of different gestational ages. The growth of the graft in situ also depended on the diabetic state of the host, and chronic hyperglycaemia appeared to impair graft function. Subsequent studies using NOD recipient mice as a model for IDDM showed that recurrent autoimmune disease was seen in foetal islet isografts but rapid rejection of allografts and foetal pig xenografts also occurred. The striking differences seen between the allo-, and xenograft response was the presence of many eosinophils that dominated the infiltrate at the xenograft site. However, HAR was not a problem in this discordant xenograft and Gal(1-3)Gal expression, the major epitope for xenoreactive Ab, was not present on differentiated cells but was detectable on ductal cells. A brief treatment with a specific anti-CD4 MAb (GK1.5) had a profound effect in the survival of xenografts in NOD mice. There were consistent differences in xenograft survival and in the number of circulating T and B cells in other strains of mice, e.g. CBA, BALB/c, C57BL/6 compared to NOD mice. Prolongation of xenograft survival for up to 12 weeks was achieved with the use of peri-transplant and weekly treatment with anti-CD4 or anti-CD3 MAbs especially when the graft has been "immunomodulated" by using 90% O2 in organ culture. Using this protocol foetal pig xenografts maturing under the kidney capsule of spontaneously diabetic NOD mice reversed hyperglycaemia and appeared also to secrete growth factor(s) that induced regeneration of cells in the host pancreas.