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Donor-derived anti-HLA antibody following allogeneic bone marrow transplantation
33
Abstracts
6.2
HOST-REACTIVE HELPER T LYMPHOCYTE PRECURSOR FREQUENCY CORRELATES WITH SURVIVAL BUT NOT WITH GVHD POST T CELL DEPLETED MARROW TRANSPLANT. CA Keever-Taylor, Y Kawanishi, T Wank, M Chaltry and LA Baxter-Lowe. BMT Programs, Medical College of Wisconsin, Milwaukee, WI and University of South Carolina, Columbia, SC. The dose of T cells infused with the marrow graft together with the host-directed allocytolytic potential of the infused cells have been previously shown by us to be associated with aGvHD and transplant survival, respectively. We have expanded our analysis to include assessment of donor-derived host~reactive 1L~2 secreting HTLp at the time of transplant (N=28). The HTLp assay was designed so as to be insensitive to minor HA differences. Each patient received marrow from an unrelated or partially matched family donor which was TCD by complement mediated lysis with the TCRa13~ specific T loB9 mAb. All donors and recipients were lILA typed by serology and one dimensional IEF for Class I and by high resolution oligotyping for Class II. Sequencing is in progress for full characterization of A, B, and DR alleles. The data show a strong correlation ofHTLp with survival with only 20% (3 of 15 pats) surviving when HTLp frequencies were ~ 1: 14,000 as compared with 5 of 8 pats surviving with frequencies between 1:14,000 and 1:100,000 and 4 of 5 pats in the group with :5;1:100,000 HTLp (p=O.02). The dose of HTLp and CTLp infusedlkg was estimated from the frequency of clonable T cells after TCD and was found to be higher in pats who did not survive, most significant was the combination of HTLp and CTLp infusedlkg (p=0.05). Neither HTLp frequency nor dose was associated with aGvHD or cGvHD in this group. Patients with no identified lILA disparities had the lowest frequencies of both HTLp and CTLp and patients with Class I and Class II disparities had the highest frequencies. Disparities involving DRB 1 elicited the highest HTLp responses, although high frequencies were also seen with apparent Class I disparities only. These data support the hypothesis that post BMT complications may be influenced not only by T cell dose but by the alloreactive potential of the cells infused. Patients. whose donors have high levels of both host~reactive CTLp and HTLp appear to be at greatest risk.
6.2
DONOR-DERIVED ANTI-HLA ANTmODY FOLLOWING ALLOGENEIC BONE MARROW TRANSPLANTATION. 1M McConnack, R Bray, J Wingard, S Devine and G Rodey, Dept. Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA. Antibody responses to recall antigens can be adoptively transferred following allogeneic bone marrow transplantation (allo~BMT). Recipient immunoglobulin (Ig) production of donor origin after allo~ BMT has been illustrated in studies of memory responses to vaccines and conversion to donor Ig allotype. Similarly, we report three patients who exhibited donor~derived HLA antibody following allo-BMT. Two patients received allo-BMT from genotypically HLA-identical siblings and one from a matched unrelated donor. All three donors were parous females and prospective donor antibody screening demonstrated anti-HLA antibodies with defined specificity. AHG-CDC or flow cytometric antibody analyses of recipient sera following allo~BMT revealed anti-HLA antibody appearing at day 10, day 20 or day 28. Antibody specificity analysis and the rapid appearance of the antibodies strongly suggest an anamnestic response of donor origin. The source of challenging alloantigen for the anamnestic response would be most likely from supportive blood products (ie. platelets) given post allo-BMT. The anti-HLA antibodies were short-lived, all disappearing by 6 months post allo-BMT. These data are supportive of the likely development of anti-HLA antibody in recipients post allo-BMT when the donor has a history of alloimmunization. Furthennore, this study supports the use of routine antibody screening of sensitized donors (ie. parous females) to identify recipients at risk for developing anti-HLA antibodies and thus becoming immunologically refractory to random platelets.
Abstracts
6.2
HOST-REACTIVE HELPER T LYMPHOCYTE PRECURSOR FREQUENCY CORRELATES WITH SURVIVAL BUT NOT WITH GVHD POST T CELL DEPLETED MARROW TRANSPLANT. CA Keever-Taylor, Y Kawanishi, T Wank, M Chaltry and LA Baxter-Lowe. BMT Programs, Medical College of Wisconsin, Milwaukee, WI and University of South Carolina, Columbia, SC. The dose of T cells infused with the marrow graft together with the host-directed allocytolytic potential of the infused cells have been previously shown by us to be associated with aGvHD and transplant survival, respectively. We have expanded our analysis to include assessment of donor-derived host~reactive 1L~2 secreting HTLp at the time of transplant (N=28). The HTLp assay was designed so as to be insensitive to minor HA differences. Each patient received marrow from an unrelated or partially matched family donor which was TCD by complement mediated lysis with the TCRa13~ specific T loB9 mAb. All donors and recipients were lILA typed by serology and one dimensional IEF for Class I and by high resolution oligotyping for Class II. Sequencing is in progress for full characterization of A, B, and DR alleles. The data show a strong correlation ofHTLp with survival with only 20% (3 of 15 pats) surviving when HTLp frequencies were ~ 1: 14,000 as compared with 5 of 8 pats surviving with frequencies between 1:14,000 and 1:100,000 and 4 of 5 pats in the group with :5;1:100,000 HTLp (p=O.02). The dose of HTLp and CTLp infusedlkg was estimated from the frequency of clonable T cells after TCD and was found to be higher in pats who did not survive, most significant was the combination of HTLp and CTLp infusedlkg (p=0.05). Neither HTLp frequency nor dose was associated with aGvHD or cGvHD in this group. Patients with no identified lILA disparities had the lowest frequencies of both HTLp and CTLp and patients with Class I and Class II disparities had the highest frequencies. Disparities involving DRB 1 elicited the highest HTLp responses, although high frequencies were also seen with apparent Class I disparities only. These data support the hypothesis that post BMT complications may be influenced not only by T cell dose but by the alloreactive potential of the cells infused. Patients. whose donors have high levels of both host~reactive CTLp and HTLp appear to be at greatest risk.
6.2
DONOR-DERIVED ANTI-HLA ANTmODY FOLLOWING ALLOGENEIC BONE MARROW TRANSPLANTATION. 1M McConnack, R Bray, J Wingard, S Devine and G Rodey, Dept. Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA. Antibody responses to recall antigens can be adoptively transferred following allogeneic bone marrow transplantation (allo~BMT). Recipient immunoglobulin (Ig) production of donor origin after allo~ BMT has been illustrated in studies of memory responses to vaccines and conversion to donor Ig allotype. Similarly, we report three patients who exhibited donor~derived HLA antibody following allo-BMT. Two patients received allo-BMT from genotypically HLA-identical siblings and one from a matched unrelated donor. All three donors were parous females and prospective donor antibody screening demonstrated anti-HLA antibodies with defined specificity. AHG-CDC or flow cytometric antibody analyses of recipient sera following allo~BMT revealed anti-HLA antibody appearing at day 10, day 20 or day 28. Antibody specificity analysis and the rapid appearance of the antibodies strongly suggest an anamnestic response of donor origin. The source of challenging alloantigen for the anamnestic response would be most likely from supportive blood products (ie. platelets) given post allo-BMT. The anti-HLA antibodies were short-lived, all disappearing by 6 months post allo-BMT. These data are supportive of the likely development of anti-HLA antibody in recipients post allo-BMT when the donor has a history of alloimmunization. Furthennore, this study supports the use of routine antibody screening of sensitized donors (ie. parous females) to identify recipients at risk for developing anti-HLA antibodies and thus becoming immunologically refractory to random platelets.