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OR6 Increased reliance on the virtual crossmatch under the new kidney allocation schema (KAS)
6
OR6
Abstracts / Human Immunology 76 (2015) 1–37
INCREASED RELIANCE ON THE VIRTUAL CROSSMATCH UNDER THE NEW KIDNEY ALLOCATION SCHEMA (KAS). Ronald F. Parsons, Howard M. Gebel, Nicole A. Turgeon, Robert A. Bray. Emory University, Atlanta, GA, United States. Aim: On 12/4/2014, the OPTN implemented a new KAS for deceased donor (DD) transplantation. Among the many changes was increased priority for highly sensitized (HS) candidates (cPRA99%). Such candidates now have the highest priority for national (100%) and regional (99%) sharing. Initial OPTN data indicate that these candidates receive 15% of all DD transplants. While the new KAS has introduced broader sharing, it has also presented new logistical and time-sensitive challenges. Therefore, we sought to assess the utility of the virtual crossmatch (vXM) in the new KAS. Methods: Between 12/04/2014 and 3/27/2015, we performed 64 DD transplants. Among transplanted patients with cPRA 99%, we assessed whether the transplant was performed based on a prospective, physical crossmatch (pXM) or vXM. The vXM was defined as the absence of donor specific antibody. For all vXM-based transplants, we reviewed results of the retrospective pXM, graft function and episodes of early rejection. Results: During this time period, 24/64 (37.5%) of the DD transplants were performed in HS candidates. Among this group, 23/24 (96%) kidneys were imported and 16 (66.6%) were transplanted solely on a prospective vXM to minimize cold ischemia time. For all vXM-based transplants, a pXM was performed concurrently with the transplant. In no instance was the pXM unexpectedly positive due to HLA antibody. Most importantly, there were no instances of hyperacute or accelerated graft rejection among any of the HS candidates transplanted based on a vXM. Conclusions: Due to the new KAS, centers are now receiving more organ offers for HS patients. Frequently, offers come from centers at great distances and often there is insufficient time to ship material for a prospective pXM. Rather, centers must accept or decline what may be a patient’s only opportunity for a compatible organ, solely on a vXM. Additionally, vXM-based transplantation minimizes cold ischemia time. Our data demonstrate that a vXM can identify HS candidates who can proceed safely to transplant without a prospective pXM. Limitations to performing a vXM include; incomplete/incorrect donor HLA type, lack of current patient serum or equivocal donor specific antibodies. Nonetheless, the vXM can prove beneficial for allocating organs to the most disadvantaged candidates.
OR7
ANTIBODIES TO MHC CLASS I INDUCE TRANSCRIPTION FACTOR ZBA0000000 AND REGULATE DEVELOPMENT OF AUTOIMMUNITY LEADING TO CHRONIC REJECTION. Deepak Nayak, Fangyu Zhou, Monal Sharma, Zhongping Xu, Andrew Gelman, Thalachallour Mohanakumar. Washington University School of Medicine, St. Louis, MO, United States. Aim: Chronic rejection, bronchiolitis obliterans syndrome (BOS), is a major hurdle following human lung transplantation. Antibodies (Ab) to HLA (DSA) and lung-associated antigens (Collagen V (Col-V) and K-alpha-1 Tubulin (Ka1T) have been associated with development of BOS. Our goal was to demonstrate early events (genes and their role in inflammation) associated with administration of anti-MHC class I (H-2 Kb) into murine (C57BL/6) lungs that precede cellular and humoral autoimmunity and chronic rejection. Methods: We analyzed molecular signatures arising from anti-MHC administration by genechip microarray. Zba0000000 was selected for functional analysis. siRNA-Lentivirus was used to knockdown Zba0000000 in lungs to study its role in Ab induced chronic rejection. Kinetics of Ab development and T cell responses was tested by ELISA and ELISPOT. Changes in leukocyte profile were analyzed by flow cytometry and gene expression levels by real-time PCR. Results: In genechip assay, 12 genes including Zba0000000 were significantly (p < 0.005) upregulated (>1.5-fold) at 4 h post Ab administration. Use of siRNA-Lentivirus knocked down Zba0000000 expression. Following anti-MHC I, Zba0000000 knockdown demonstrated significant (p < 0.001) reduction in anti-Ka1T and anti-Col-V, and remained free from inflammation and fibrosis. Further, anti-MHC elicited lower Ka1T and Col-V specific Th17 and Th1 cells. Moreover, less infiltration of neutrophil and B cell were seen in lungs and decreased levels of B cell (CXCL13) and neutrophil (CXCL15) chemoattractants were observed. Conclusions: We demonstrate that DSA activates unique molecular signature involved in lung autoimmunity. Zba0000000, as a transcription factor induced by DSA, is a ‘‘master regulator’’ of B and T cell development and has novel inflammatory functions leading to chronic rejection. By targeted knockdown, we established that Zba0000000 has an obligatory role in the amplification of inflammatory circuits where its loss rendered protection from Ab induced obliterative airway disease.
OR6
Abstracts / Human Immunology 76 (2015) 1–37
INCREASED RELIANCE ON THE VIRTUAL CROSSMATCH UNDER THE NEW KIDNEY ALLOCATION SCHEMA (KAS). Ronald F. Parsons, Howard M. Gebel, Nicole A. Turgeon, Robert A. Bray. Emory University, Atlanta, GA, United States. Aim: On 12/4/2014, the OPTN implemented a new KAS for deceased donor (DD) transplantation. Among the many changes was increased priority for highly sensitized (HS) candidates (cPRA99%). Such candidates now have the highest priority for national (100%) and regional (99%) sharing. Initial OPTN data indicate that these candidates receive 15% of all DD transplants. While the new KAS has introduced broader sharing, it has also presented new logistical and time-sensitive challenges. Therefore, we sought to assess the utility of the virtual crossmatch (vXM) in the new KAS. Methods: Between 12/04/2014 and 3/27/2015, we performed 64 DD transplants. Among transplanted patients with cPRA 99%, we assessed whether the transplant was performed based on a prospective, physical crossmatch (pXM) or vXM. The vXM was defined as the absence of donor specific antibody. For all vXM-based transplants, we reviewed results of the retrospective pXM, graft function and episodes of early rejection. Results: During this time period, 24/64 (37.5%) of the DD transplants were performed in HS candidates. Among this group, 23/24 (96%) kidneys were imported and 16 (66.6%) were transplanted solely on a prospective vXM to minimize cold ischemia time. For all vXM-based transplants, a pXM was performed concurrently with the transplant. In no instance was the pXM unexpectedly positive due to HLA antibody. Most importantly, there were no instances of hyperacute or accelerated graft rejection among any of the HS candidates transplanted based on a vXM. Conclusions: Due to the new KAS, centers are now receiving more organ offers for HS patients. Frequently, offers come from centers at great distances and often there is insufficient time to ship material for a prospective pXM. Rather, centers must accept or decline what may be a patient’s only opportunity for a compatible organ, solely on a vXM. Additionally, vXM-based transplantation minimizes cold ischemia time. Our data demonstrate that a vXM can identify HS candidates who can proceed safely to transplant without a prospective pXM. Limitations to performing a vXM include; incomplete/incorrect donor HLA type, lack of current patient serum or equivocal donor specific antibodies. Nonetheless, the vXM can prove beneficial for allocating organs to the most disadvantaged candidates.
OR7
ANTIBODIES TO MHC CLASS I INDUCE TRANSCRIPTION FACTOR ZBA0000000 AND REGULATE DEVELOPMENT OF AUTOIMMUNITY LEADING TO CHRONIC REJECTION. Deepak Nayak, Fangyu Zhou, Monal Sharma, Zhongping Xu, Andrew Gelman, Thalachallour Mohanakumar. Washington University School of Medicine, St. Louis, MO, United States. Aim: Chronic rejection, bronchiolitis obliterans syndrome (BOS), is a major hurdle following human lung transplantation. Antibodies (Ab) to HLA (DSA) and lung-associated antigens (Collagen V (Col-V) and K-alpha-1 Tubulin (Ka1T) have been associated with development of BOS. Our goal was to demonstrate early events (genes and their role in inflammation) associated with administration of anti-MHC class I (H-2 Kb) into murine (C57BL/6) lungs that precede cellular and humoral autoimmunity and chronic rejection. Methods: We analyzed molecular signatures arising from anti-MHC administration by genechip microarray. Zba0000000 was selected for functional analysis. siRNA-Lentivirus was used to knockdown Zba0000000 in lungs to study its role in Ab induced chronic rejection. Kinetics of Ab development and T cell responses was tested by ELISA and ELISPOT. Changes in leukocyte profile were analyzed by flow cytometry and gene expression levels by real-time PCR. Results: In genechip assay, 12 genes including Zba0000000 were significantly (p < 0.005) upregulated (>1.5-fold) at 4 h post Ab administration. Use of siRNA-Lentivirus knocked down Zba0000000 expression. Following anti-MHC I, Zba0000000 knockdown demonstrated significant (p < 0.001) reduction in anti-Ka1T and anti-Col-V, and remained free from inflammation and fibrosis. Further, anti-MHC elicited lower Ka1T and Col-V specific Th17 and Th1 cells. Moreover, less infiltration of neutrophil and B cell were seen in lungs and decreased levels of B cell (CXCL13) and neutrophil (CXCL15) chemoattractants were observed. Conclusions: We demonstrate that DSA activates unique molecular signature involved in lung autoimmunity. Zba0000000, as a transcription factor induced by DSA, is a ‘‘master regulator’’ of B and T cell development and has novel inflammatory functions leading to chronic rejection. By targeted knockdown, we established that Zba0000000 has an obligatory role in the amplification of inflammatory circuits where its loss rendered protection from Ab induced obliterative airway disease.