Involvement of platelet-derived growth factor and histocompatibility of DRB 1 in chronic renal allograft nephropathy.
BACKGROUND
The role of activated T cells in graft arteriosclerosis, which is observed in chronic renal allograft nephropathy, and the involvement of major histocompatibility complex (MHC) incompatibility remain to be determined. We examined the effect of T lymphocytes that were obtained from renal transplant patients undergoing chronic rejection treated with cyclosporine (CsA) on platelet-derived growth factor (PDGF)-induced proliferation of cultured human vascular smooth muscle cells (SMC) and compared the proliferation activity of T lymphocytes with MHC incompatibility, especially DRB 1 mismatch.


METHODS
Renal transplant patients with continued allograft function, who survived more than 1 year after transplantation, were recruited. Chronic rejection was documented by graft-biopsy findings together with increasing serum creatinine levels (10-20% per year). After the incubation of supernatant (conditioning medium) of cultured T cells from CsA-treated renal transplant patients with chronic rejection (n=18) and with normal renal function (n=14) as control, normal subjects (n=11) and chronic hemodialysis (HD) patients (n=5) with cultured SMC in the presence or absence of PDGF, DNA synthesis (3H-thymidine uptake) of SMC was examined. The in vitro effects of CsA on DNA synthesis of cultured SMC were also evaluated.


RESULTS
The supernatant of cultured T cells from renal transplant patients with chronic rejection stimulated PDGF-induced DNA synthesis of SMC in a dose-dependent manner, showing significant enhancement as compared with control transplant patients, normal subjects, and chronic HD patients. The supernatant itself did not significantly stimulate DNA synthesis of SMC. No significant in vitro stimulation of CsA on DNA synthesis was observed. The supernatant of T cells obtained from recipients undergoing chronic rejection with two DRB 1 mismatches showed significantly higher enhanced activity of PDGF-induced DNA synthesis than the supernatant from those recipients without mismatch of DRB 1. On the other hand, no significant correlation of the enhanced activity by T cell supernatant to HLA A and B mismatch numbers was observed.


CONCLUSIONS
Growth factor-promoting factors(s) derived from activated T cells associated with MHC class II DR expression, which promotes PDGF-induced proliferation of SMC, exists in renal transplant patients with chronic renal allograft nephropathy, and is probably involved in arteriosclerosis of the graft kidney.
Yamada
K
K
Sakura National Hospital (National Kidney Transplantation Center, Japan), Division of Clinical Research, Chiba. kyamada@snh.hosp.go.jp
Hatakeyama
E
E
Sakamaki
T
T
Nishimura
M
M
Arita
S
S
Sakamoto
K
K
Hamaguchi
K
K
Nakajima
K
K
Otsuka
M
M
Tanabe
K
K
D000328:Adult; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016572:Cyclosporine / Q000627:therapeutic use; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis*; D059811:HLA-DRB1 Chains; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007674:Kidney Diseases / Q000209:etiology* / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D014184:Transplantation, Homologous
D017077:Culture Media, Conditioned; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D016572:Cyclosporine; D004247:DNA