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A new insight into the transfusion paradigm
123
Abstracts
6.9 #160
6.9 #161
ONE HLA-DR MISMATCH (MM) IS SUFFICIENT TO INDUCE OPTIMAL IL-lO SECRETlON DURING MLR. M. Toungouz], C. Denys], D. De Groote2 , M. Andrien] and E. Dupont]. ] Department of Immunology, Erasme Hospital and 2 Medgenix, Brussels, Belgium. Several studies have shown that one HLA-DR matched pretransplantation blood transfusions improve allograft survival. This effect is poorly understood. Active suppressor mechanisms have been invoked. IL-IO is a cytokine (CK) produced by Th2 cells that inhibits IFN-y and TNF-a production and the allogeneic proliferative response. We have previously shown that TNF-a. production during MLR was controlled by DR differences. The amount of CK' release was graded according to the level of DR incompatibility. MLRs involving subjects differing by two DR MM produced significantly higher TNFa. levels as compared to one DR MM pairs. The present study was designed to investigate the influence of one vs two DR differences on IL-lO production during MLR. IL-lO was measured by a highly sensitive ELISA assay (min detectable conc:lpg/ml). In MLRs involving HLA different subjects (n=22), a significant IL-lO release was observed at day 5 (35.9±5 pg/ml). Addition of anti-IL-IO Ab resulted in strong enhancement of both IFN-y and TNF-a. productions. Furthermore, alloactivation primed monomacrophages to LPS which considerably enhanced IL-lO production (575±59 pg/ml in MLR vs 209±20 in autologous controls. p
A NEW INSIGHT INTO TIffi TRANSFUSION PARADIGM A Jackson, SAlmond, C McSherry, K Butters, M Diko, B Grahs, AJ Matas, NL Reinsmoen, University of Minnesota, Minneapolis,MN. The role of donor-specific transfusions (tfu) in allograft acceptance is controversial. One reason for the discrepancy in the understanding of the "tfu effect" may be that there are juxtaposed mechanisms at work involving HLA-DR. We studied a group of transfused kidney allograft recipients (both living related and cadaver donors) and the effect of pretransplant blood tfus with regard to the detection of peripheral blood microchimerism (PBMC), the development of donor-antigen specific hyporesponsiveness (DASH), and HLADR sharing with both kidney and blood donor. Kidney recipients, previously nontrans~ed, received 2 (150 ml) HLA-DR typed leukopoor random blood units I to 8 months pretransplant. Azathioprine began on the day of tfn and continued for 2 weeks. None of these recipients was sensitized, as indicated by a 0% PRA. A PBMC detection assay was performed 2 weeks posttransfusion, using a radioactive PCR-SSP protocol for the disparate donor DR. Posttransplant blood samples were later obtained and assayed for DASH. We define DASH as a significant reduction in the proliferative response to donor class II antigens; it is associated with improved long-term graft survival. Five recipients received blood units that shared I DR antigen with the kidney donor but none with the recipient. Of these 5 recipients, 3 tested positive for PBMC pretransplant (1 was lUlevaluable), and 4 developed DASH (p=.021 0). Recipients who were not exposed to a shared donor antigen in the transfusate, or who were exposed but shared a DR antigen with that tfu unit, did not develop DASH or PBMC. Previously reported data suggested that a tfu unit sharing one DR with the donor and the second with the recipient increased graft survival, due to the down regulation of the cellular (and presumably humoral) anti-alloimmune response. Our data suggests a beneficial effect of receiving a tfu unit that contains a shared donor DR ~u~ not a shared recipient DR. Both the recIpIent and donor T-cell repertoires are composed ofT -cells restricted to their own DR; thus, an absence of a shared DR with the tfu unit ( removal of the indirect pathway) may increase the survival of donor cells in the recipient. This may, in turn, enhance microchimerism and perhaps the development of DASH.
p=0.0210
Donor DR in Transfusion Unit
+ -+ DASH & PBMC
5 (0 DR matched unit)
-
2
J1 DR matched unit)
0 7
Abstracts
6.9 #160
6.9 #161
ONE HLA-DR MISMATCH (MM) IS SUFFICIENT TO INDUCE OPTIMAL IL-lO SECRETlON DURING MLR. M. Toungouz], C. Denys], D. De Groote2 , M. Andrien] and E. Dupont]. ] Department of Immunology, Erasme Hospital and 2 Medgenix, Brussels, Belgium. Several studies have shown that one HLA-DR matched pretransplantation blood transfusions improve allograft survival. This effect is poorly understood. Active suppressor mechanisms have been invoked. IL-IO is a cytokine (CK) produced by Th2 cells that inhibits IFN-y and TNF-a production and the allogeneic proliferative response. We have previously shown that TNF-a. production during MLR was controlled by DR differences. The amount of CK' release was graded according to the level of DR incompatibility. MLRs involving subjects differing by two DR MM produced significantly higher TNFa. levels as compared to one DR MM pairs. The present study was designed to investigate the influence of one vs two DR differences on IL-lO production during MLR. IL-lO was measured by a highly sensitive ELISA assay (min detectable conc:lpg/ml). In MLRs involving HLA different subjects (n=22), a significant IL-lO release was observed at day 5 (35.9±5 pg/ml). Addition of anti-IL-IO Ab resulted in strong enhancement of both IFN-y and TNF-a. productions. Furthermore, alloactivation primed monomacrophages to LPS which considerably enhanced IL-lO production (575±59 pg/ml in MLR vs 209±20 in autologous controls. p
A NEW INSIGHT INTO TIffi TRANSFUSION PARADIGM A Jackson, SAlmond, C McSherry, K Butters, M Diko, B Grahs, AJ Matas, NL Reinsmoen, University of Minnesota, Minneapolis,MN. The role of donor-specific transfusions (tfu) in allograft acceptance is controversial. One reason for the discrepancy in the understanding of the "tfu effect" may be that there are juxtaposed mechanisms at work involving HLA-DR. We studied a group of transfused kidney allograft recipients (both living related and cadaver donors) and the effect of pretransplant blood tfus with regard to the detection of peripheral blood microchimerism (PBMC), the development of donor-antigen specific hyporesponsiveness (DASH), and HLADR sharing with both kidney and blood donor. Kidney recipients, previously nontrans~ed, received 2 (150 ml) HLA-DR typed leukopoor random blood units I to 8 months pretransplant. Azathioprine began on the day of tfn and continued for 2 weeks. None of these recipients was sensitized, as indicated by a 0% PRA. A PBMC detection assay was performed 2 weeks posttransfusion, using a radioactive PCR-SSP protocol for the disparate donor DR. Posttransplant blood samples were later obtained and assayed for DASH. We define DASH as a significant reduction in the proliferative response to donor class II antigens; it is associated with improved long-term graft survival. Five recipients received blood units that shared I DR antigen with the kidney donor but none with the recipient. Of these 5 recipients, 3 tested positive for PBMC pretransplant (1 was lUlevaluable), and 4 developed DASH (p=.021 0). Recipients who were not exposed to a shared donor antigen in the transfusate, or who were exposed but shared a DR antigen with that tfu unit, did not develop DASH or PBMC. Previously reported data suggested that a tfu unit sharing one DR with the donor and the second with the recipient increased graft survival, due to the down regulation of the cellular (and presumably humoral) anti-alloimmune response. Our data suggests a beneficial effect of receiving a tfu unit that contains a shared donor DR ~u~ not a shared recipient DR. Both the recIpIent and donor T-cell repertoires are composed ofT -cells restricted to their own DR; thus, an absence of a shared DR with the tfu unit ( removal of the indirect pathway) may increase the survival of donor cells in the recipient. This may, in turn, enhance microchimerism and perhaps the development of DASH.
p=0.0210
Donor DR in Transfusion Unit
+ -+ DASH & PBMC
5 (0 DR matched unit)
-
2
J1 DR matched unit)
0 7