Importance of donor-derived lymphocytes in the protection of pancreaticoduodenal or islet grafts from recurrent autoimmunity: a role for RT6+NKR-P1+ T cells.
BACKGROUND
A rat pancreas transplantation model with insulin-dependent diabetes mellitus (IDDM) recurrence was established using a Wistar-Furth (WF; RT1u, RT6.2) rat as a donor and diabetes-prone (DP; RT1u, rt6.1 gene carrier) BioBreeding rat as a recipient. Interestingly, NKR-P1+TCRalphabeta+ (NKT) cells have recently been reported to have immunoregulatory functions in preventing autoimmune diabetes. The purpose of this study was to specifically examine the contribution of NKT cells in the prevention of IDDM recurrence.


METHODS
Graft survivals with or without anti-intercellular adhesion molecule-1/leukocyte function-associated antigen-1 monoclonal antibodies were examined comparing pancreaticoduodenal (PD) transplantation with islet transplantation or pancreas-alone transplantation excluding duodenum and peripancreatic lymph nodes, in an IDDM recurrent model. The cells of the spleen were analyzed by flow cytometry (including intracellular interleukin (IL)-4 analysis), and serum cytokine levels (IL-4 and interferon-gamma) were determined by enzyme-linked immunosorbent assays (ELISA).


RESULTS
Only those DP recipients transplanted with PD grafts with monoclonal antibody treatment were free from IDDM. Flow cytometric analyses of spleen cells showed that NKT cells in them, compared with those in the recurrent DP recipients (mean <7%), increased significantly (13.7+/-3.1% in the total splenic T cells), most of which (85.9+/-4.3%) were derived from the donor (RT6.2+). The absolute number of RT6+NKT cells significantly increased in the nonrecurrent DP recipients, whereas that of RT6-NKT cells was similar with those of the other recurrent DP recipients. These RT6+NKT cells were predominantly CD4+ and showed significantly more expressions of intracellular IL-4 than the other T cells. By ELISA, serum interferon-gamma was not detectable (< 13 pg/ml) in any of the rats. However, IL-4 was detected at 111.6+/-47.8 pg/ml only in the nonrecurrent DP recipients.


CONCLUSIONS
Unlike islet or pancreas-alone transplants, NKT cells, especially RT6+NKT cells derived from PD grafts, may have an important immunoregulatory function of preventing IDDM recurrence, involving a Th2 deviation.
Department of Bioregulation, Biomedical Research Center, Osaka University Graduate School of Medicine, Japan.
M
M
Tori
T
T
Ito
S
S
Kitagawa-Sakakida
M
M
Nozawa
H
H
Matsuda
R
R
Shirakura
D036002:ADP Ribose Transferases / Q000032:analysis*; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface / Q000032:analysis*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004386:Duodenum / Q000637:transplantation*; D005434:Flow Cytometry; D015847:Interleukin-4 / Q000032:analysis; D016381:Islets of Langerhans Transplantation; D037181:Lectins, C-Type; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016035:Pancreas Transplantation; D051381:Rats; D011920:Rats, Inbred WF; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015847:Interleukin-4; D036002:ADP Ribose Transferases; C449322:Art2a protein, mouse; C449339:Art2b protein, mouse; C090163:Art2b protein, rat