Prolonged survival of donor skin grafts on mice bearing established islet of Langerhans transplants.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D L Faustman
Publications and source records attributed to D L Faustman.
Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody.
Previously we have demonstrated that islets of Langerhans treated with donor-specific anti-Ia serum and complement survive when transplanted across the major histocompatibility complex of the mouse. In this study, using immunofluorescence, we demonstrate two morphologically distinct populations of Ia-positive cells scattered within the Ia-negative islet tissue. A large irregularly shaped Ia-positive subset of cells were identified as dendritic cells by using the 33D1 antibody specific for a mouse dendritic cell antigen. The other small, round Ia-positive subset was 33D1 negative. Islets pretreated with anti-dendritic cell antibody and complement prior to transplantation survived in their histoincompatible recipients for greater than 200 days. Rejection of stable islet allografts promptly occurred when transplant recipients were challenged with 1 X 10(5) donor dendritic cells 60 days after transplantation. These results demonstrate an important in vivo role for donor dendritic cells in the stimulation of allograft rejection.
Animals↗
Implications of altered apoptosis in diabetes mellitus and autoimmune disease.
Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development requires cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accetuated apoptosis, are now demonstrated as central defects in diverse human and murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor CD95 (Fas) and its ligand CD95L (FasL) have been identified; these errors create a lymphoid system resistant to apoptosis. In contract, select lymphoid subpopulations of auto immune diabetic mice have accelerated apoptosis due to faulty activation of transcription factor NF-kappaB that normally protects against apoptotic death. The genetic basis of interrupted NF-kappaB in diabetes is a gene defect in an essential subunit of the proteasome. Although no specific gene in most common forms of human autoimmune disease has been identified, functional assays repeatedly demonstrate apoptotic defects in multiple cellular signaling pathways for cell death.
Animals↗
Occult CD45 T cell developmental defect in type 1 diabetes.
Individuals with insulin-dependent diabetes mellitus, as well as high-risk prediabetic subjects who are identified prior to the onset of hyperglycaemia by abnormal autoantibodies to both insulin and islet cells have an autologous antigen presenting cell (APC) defect that results in sluggish T cell proliferation in the in vitro autologous mixed lymphocyte reaction (AMLR). In contrast, lower-risk relatives, who produce autoantibodies restricted to insulin and fail to develop overt hyperglycaemia, show apparently normal autologous antigen presenting cell function and paradoxically demonstrate excessive T cell proliferation in the AMLR. We have now characterized this lower-risk vigorous T cell response in the autologous mixed by lymphocyte reaction as a predominant and excessive proliferation of CD4+ T cells to self-antigens (n = 10, p < 0.001). In addition, the normal autologously driven transition of the expanding CD45RA+ subset of CD4+ cells into transient CD45RA+RO+ cells with subsequent progression to CD45RA-RO+ cells is partially blocked in the lower-risk autologous response compared to controls (n = 5, p = 0.01, respectively). Autologously driven T cell developmental transitions also appear to be blocked in these individuals in vitro; the peripheral blood of lower-risk relatives contains an increased number of CD4+ cells abnormally coexpressing CD45RA and CD45RO (p = 0.01). Interestingly, in two twin sets reconstitution of T cells from the diabetic twin of an identical twin-pair that is discordant for Type 1 diabetes with the APCs of the nondiabetic twin resulted in overly vigorous T cell proliferation dominated by CD4+ cells; phenotypically, these CD4+ cells at the end of the reaction were similar to those of lower-risk relatives in that the CD45RA+RO+ transition into CD45RA-RO+ cells was now observed to be defective. Therefore, T cells from lower-risk relatives and individuals with Type 1 diabetes appear to possess similar intrinsic T cell developmental defects in CD45 transitions that are apparent after normal autologous antigen stimulation.
Adolescent↗