- Email: [email protected]
nonresponder status
150
Abstracts
RETROPLACENTAL GAMMA GLOBULIN (RPGG) INHIBITS ALLOANTIBODIES DIRECTED AT CLASS I AND CLASS II HLA ANTIGENS. M. Fotino, M. Suthanthiran, R. Riggio, and K.H. Stenzel; Rogosin Institute, Depts. Medicine and Biochemistry, Cornell University Medical College, New York, N Y R P G G , in a prospective controlled study of 208 cadaver kidney graft recipients, significantly improved renal allograft survival rates (Transplantation 33:636, 1982). Superior graft survival rates were found even in sensitized recipients and in those receiving second grafts suggesting a beneficial modulation of pre-existing humoral immunity. We therefore examined RPGG's effect on defined alloantibodies directed at class I and II antigens in a C' dependent microcytotoxicity assay. Using 1 /21 R P G G (test) or IgG (control); 1/zl anti-HLA serum (3-8 sera/specificity); 30 min incubation at 37°C; 1~1 lymphocyte suspension (4-8 panel cells/HLA specificity); 30 min incubation at 22°C; 1 wash (PBS); 5/zl diluted rabbit serum as complement source; 1-hr incubation at 22°C, dye, formalin. The results were that: (1) control IgG did not inhibit any HLA antisera tested (>4000 tests); (2) RPGG, by itself, was not cytotoxic to the panel cells; (3) R P G G did inhibit 5 0 - 1 0 0 % of anti-class I antibodies of each HLA specificities tested; (4) Of class II specificities, only anti-DR4, DRw6, DRw52, DRw53, and DQ1 were inhibited by RPGG. Inhibition of alloantibody binding to target cells and/or neutralization of alloantibody (anti-idiotypic activity) might be responsible for the inhibitory effect of RPGG. Therapeutic benefits of R P G G may be related to its ability to intercept the cytotoxic activities of antibodies directed to HLA. CORRELATION BETWEEN ACUTE GRAFT VS. HOST DISEASE (GVHD) AND MATCHING FOR PUBLIC CLASS I EPITOPES IN PATIENTS RECEIVING ONE-LOCUS INCOMPATIBLE HAPLOIDENTICAL BONE MARROW TRANSPLANTS. P.G. Beatty, B. Nisperos, E. Mickelson, E.D. Thomas, and J.A. Hansen; Fred Hutchinson Cancer Research Center: Puget Sound Blood Center, Seattle, WA Patients receiving one locus incompatible transplants from a haploidentical relative are known to be at increased risk for acute G V H D (61%) compared to patients receiving transplants from an HLA genotypically identical sibling (39%). Our routine definition of one locus incompatibility is based on assignment of private antigen specificities ( W H O defined). It is possible, however, that private allele-specific epitopes may not be as important as epitopes with public specificity. To test this hypothesis, we reclassified our one locus, class I HLA-A or B incompatible bone marrow transplants (n -- 61) into those incompatible for a public epitope (n = 24) and those compatible for a public epitope (n = 37). The public epitope system utilized was based on a consensus of serological analyses resulting from the American Workshop organized by Fuller and Rodey. We found that patients receiving public incompatible grafts had a rate of G V H D of 83% whereas patients receiving public compatible grafts had a rate of G V H D of 59%. This decreased risk of G V H D in public compatible transplants was significant (p = 0.022). These findings indicate that all class I allelic differences do not have equal impact on G V H D , and suggest that identification of other functionally relevant epitopes such as those defined by T-cell recognition might more closely correlate with G V H D . MULTIPLE KIDNEY TRANSPLANTS: CYCLOSPORINE, MATCHING, AND RESPONDER/ NONRESPONDER STATUS. James Cicciarelli, J.M. Cecka, and P.I. Terasaki; UCLA Tissue Typing Laboratory, Los Angeles, CA
Abstracts
151
The effects of cyclosporine A(CsA), tissue matching, and cytotoxic antibodies on cadaver kidney regraft survival were studied using data reported to the UCLA Transplant Registry. Graft survival in patients who received multiple kidneys was 58% with or without cyclosporine A (CsA). When these recipients were grouped according to the duration of their first transplant into those who lost their graft within 1 month (mixed), between 1 and 3 months (responder), and after 3 months (nonresponder), patterns in survival of the second graft emerge. Recipients whose first graft was lost between 1 and 3 months after the transplant had a 45% 1-yr survival for the second graft. If the first graft was lost after more than 3 months, the second graft had a 56% 1-yr survival. Recipients in the mixed group had 57% graft survival with CsA vs. 63% without. Responder group recipients had 53% graft survival with CsA vs. 45% without. Nonresponder group recipients had 67% graft survival with CsA vs. 59% without. HLA-AB matching had a pronounced beneficial effect on graft survival in the responder group with 65% graft survival in zero mismatched patients compared to 33% in those with 3 or 4 mismatches. In contrast, the nonresponder group had a nominal 6% increase in graft survival with matching (60% vs. 54%). When cytotoxic antibody was examined in the responder and nonresponder groups of patients, 15% more nonresponder patients had less than 10% panel reactive antibody. These data clearly show that kidney regraft recipients can be divided into immunological responder and nonresponder groups based on the duration of the first transplant. Graft survival in both groups was increased by CsA immunosuppression. HLAAB matching had a profound effect on graft survival in the responder group.
A PREDICTIVE MODEL FOR RISK OF SENSITIZATION BY DONOR-SPECIFIC TRANSFUSION. B. W. Colombe, R. P. Juster, W. Amend, O. Salvatierra, Jr., and M. R. Garovoy; Immunogenetics & Transplantation Lab., Transplant Service and Biostatistics Unit, University of California, San Francisco, CA Transfusion of renal patients with blood from their prospective specific organ donors (donor-specific transfusion-DST) poses some risk of sensitizing the recipient to donor HLA class I antigens. We have developed a statistical model for predicting the risk of sensitization of the DST recipient utilizing a sample of 233 cases who underwent DST from 1982-1985. A randomly selected "index" set of 174 cases was used to develop the model. The remaining 59 cases were used as an independent "validation" set to evaluate the performance of our predictor. Using linear logistic regression, we identified five variables in our index set as important predictors of risk (all p values < 0.05). These are: (1) history of thirdparty blood transfusion; (2) baseline panel reactive antibody (PRA) level; (3) number of HLA antigens matched; (4) previous pregnancy; and (5) treatment with Imuran. From this analysis a risk estimation equation was obtained involving these five variables which was used to compute a predicted probability of sensitization for each patient in the validation set. These observations were arranged according to the estimated probability and then divided into quintiles of risk. For each quintile, summing the predicted probabilities over all patients produced a predicted number of positive sensitizations (see table below). Using a chi-square goodness-of-fit criterion, we found extremely high agreement between the predicted and actual number of positive sensitizations (chi-square = 1.66; d.f. = 4; p = 0.8). Our predictive scheme is readily translated into a simple scale easily calculated by the clinician. Such an instrument can provide a valuable supplement to clinical judgement and a quantitative expression of sensitization risk.
Abstracts
RETROPLACENTAL GAMMA GLOBULIN (RPGG) INHIBITS ALLOANTIBODIES DIRECTED AT CLASS I AND CLASS II HLA ANTIGENS. M. Fotino, M. Suthanthiran, R. Riggio, and K.H. Stenzel; Rogosin Institute, Depts. Medicine and Biochemistry, Cornell University Medical College, New York, N Y R P G G , in a prospective controlled study of 208 cadaver kidney graft recipients, significantly improved renal allograft survival rates (Transplantation 33:636, 1982). Superior graft survival rates were found even in sensitized recipients and in those receiving second grafts suggesting a beneficial modulation of pre-existing humoral immunity. We therefore examined RPGG's effect on defined alloantibodies directed at class I and II antigens in a C' dependent microcytotoxicity assay. Using 1 /21 R P G G (test) or IgG (control); 1/zl anti-HLA serum (3-8 sera/specificity); 30 min incubation at 37°C; 1~1 lymphocyte suspension (4-8 panel cells/HLA specificity); 30 min incubation at 22°C; 1 wash (PBS); 5/zl diluted rabbit serum as complement source; 1-hr incubation at 22°C, dye, formalin. The results were that: (1) control IgG did not inhibit any HLA antisera tested (>4000 tests); (2) RPGG, by itself, was not cytotoxic to the panel cells; (3) R P G G did inhibit 5 0 - 1 0 0 % of anti-class I antibodies of each HLA specificities tested; (4) Of class II specificities, only anti-DR4, DRw6, DRw52, DRw53, and DQ1 were inhibited by RPGG. Inhibition of alloantibody binding to target cells and/or neutralization of alloantibody (anti-idiotypic activity) might be responsible for the inhibitory effect of RPGG. Therapeutic benefits of R P G G may be related to its ability to intercept the cytotoxic activities of antibodies directed to HLA. CORRELATION BETWEEN ACUTE GRAFT VS. HOST DISEASE (GVHD) AND MATCHING FOR PUBLIC CLASS I EPITOPES IN PATIENTS RECEIVING ONE-LOCUS INCOMPATIBLE HAPLOIDENTICAL BONE MARROW TRANSPLANTS. P.G. Beatty, B. Nisperos, E. Mickelson, E.D. Thomas, and J.A. Hansen; Fred Hutchinson Cancer Research Center: Puget Sound Blood Center, Seattle, WA Patients receiving one locus incompatible transplants from a haploidentical relative are known to be at increased risk for acute G V H D (61%) compared to patients receiving transplants from an HLA genotypically identical sibling (39%). Our routine definition of one locus incompatibility is based on assignment of private antigen specificities ( W H O defined). It is possible, however, that private allele-specific epitopes may not be as important as epitopes with public specificity. To test this hypothesis, we reclassified our one locus, class I HLA-A or B incompatible bone marrow transplants (n -- 61) into those incompatible for a public epitope (n = 24) and those compatible for a public epitope (n = 37). The public epitope system utilized was based on a consensus of serological analyses resulting from the American Workshop organized by Fuller and Rodey. We found that patients receiving public incompatible grafts had a rate of G V H D of 83% whereas patients receiving public compatible grafts had a rate of G V H D of 59%. This decreased risk of G V H D in public compatible transplants was significant (p = 0.022). These findings indicate that all class I allelic differences do not have equal impact on G V H D , and suggest that identification of other functionally relevant epitopes such as those defined by T-cell recognition might more closely correlate with G V H D . MULTIPLE KIDNEY TRANSPLANTS: CYCLOSPORINE, MATCHING, AND RESPONDER/ NONRESPONDER STATUS. James Cicciarelli, J.M. Cecka, and P.I. Terasaki; UCLA Tissue Typing Laboratory, Los Angeles, CA
Abstracts
151
The effects of cyclosporine A(CsA), tissue matching, and cytotoxic antibodies on cadaver kidney regraft survival were studied using data reported to the UCLA Transplant Registry. Graft survival in patients who received multiple kidneys was 58% with or without cyclosporine A (CsA). When these recipients were grouped according to the duration of their first transplant into those who lost their graft within 1 month (mixed), between 1 and 3 months (responder), and after 3 months (nonresponder), patterns in survival of the second graft emerge. Recipients whose first graft was lost between 1 and 3 months after the transplant had a 45% 1-yr survival for the second graft. If the first graft was lost after more than 3 months, the second graft had a 56% 1-yr survival. Recipients in the mixed group had 57% graft survival with CsA vs. 63% without. Responder group recipients had 53% graft survival with CsA vs. 45% without. Nonresponder group recipients had 67% graft survival with CsA vs. 59% without. HLA-AB matching had a pronounced beneficial effect on graft survival in the responder group with 65% graft survival in zero mismatched patients compared to 33% in those with 3 or 4 mismatches. In contrast, the nonresponder group had a nominal 6% increase in graft survival with matching (60% vs. 54%). When cytotoxic antibody was examined in the responder and nonresponder groups of patients, 15% more nonresponder patients had less than 10% panel reactive antibody. These data clearly show that kidney regraft recipients can be divided into immunological responder and nonresponder groups based on the duration of the first transplant. Graft survival in both groups was increased by CsA immunosuppression. HLAAB matching had a profound effect on graft survival in the responder group.
A PREDICTIVE MODEL FOR RISK OF SENSITIZATION BY DONOR-SPECIFIC TRANSFUSION. B. W. Colombe, R. P. Juster, W. Amend, O. Salvatierra, Jr., and M. R. Garovoy; Immunogenetics & Transplantation Lab., Transplant Service and Biostatistics Unit, University of California, San Francisco, CA Transfusion of renal patients with blood from their prospective specific organ donors (donor-specific transfusion-DST) poses some risk of sensitizing the recipient to donor HLA class I antigens. We have developed a statistical model for predicting the risk of sensitization of the DST recipient utilizing a sample of 233 cases who underwent DST from 1982-1985. A randomly selected "index" set of 174 cases was used to develop the model. The remaining 59 cases were used as an independent "validation" set to evaluate the performance of our predictor. Using linear logistic regression, we identified five variables in our index set as important predictors of risk (all p values < 0.05). These are: (1) history of thirdparty blood transfusion; (2) baseline panel reactive antibody (PRA) level; (3) number of HLA antigens matched; (4) previous pregnancy; and (5) treatment with Imuran. From this analysis a risk estimation equation was obtained involving these five variables which was used to compute a predicted probability of sensitization for each patient in the validation set. These observations were arranged according to the estimated probability and then divided into quintiles of risk. For each quintile, summing the predicted probabilities over all patients produced a predicted number of positive sensitizations (see table below). Using a chi-square goodness-of-fit criterion, we found extremely high agreement between the predicted and actual number of positive sensitizations (chi-square = 1.66; d.f. = 4; p = 0.8). Our predictive scheme is readily translated into a simple scale easily calculated by the clinician. Such an instrument can provide a valuable supplement to clinical judgement and a quantitative expression of sensitization risk.