BK Virus Reactivation After Double Umbilical Cord Blood Transplantation in Adults Correlates with Tregs and Delayed Reconstitution of CD4+ and CD8+ T Effector Cells
Authors: Satyanarayana Gowri , Hammond Sarah , Kim Haesook T , McDonough Sean , Brown Julia , Politikos Ioannis , Li Lequn , Viscidi Raphael , Broge Thomas , Koralnik Igor , Cutler Corey , Ballen Karen K. , Antin Joseph H. , Marty Francisco M , Ritz Jerome , Tan C Sabrina , Boussiotis Vassiliki A. 
Published: October 2019

Abstract
Abstract 4174
Umbilical cord blood transplantation (UCBT) in adults is associated with impaired immune function and increased infection-related morbidity and mortality due to lack of antigen experienced cells and delayed immune reconstitution. BK virus (BKV) is a human polyomavirus that remains latent in renal epithelial cells and can be reactivated after hematopoietic stem cell transplantation (HSCT), leading to hemorrhagic cystitis. Data regarding BKV reactivation and its association with immune reconstitution after UCBT is lacking. We evaluated the status, cellular mechanisms, and clinical implications of immune reconstitution on BK viremia in adults with hematologic malignancies undergoing double unit cord blood transplantation. Thirty-two patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by infusion of two sequential UCB grafts and GvHD prophylaxis with tacrolimus and sirolimus. The grafts were at least a 4/6 match with each other and the recipient. The results are based on 27 evaluable patients. Assessments were done prior to transplant and at 1, 2, 3, 6 and 12 months after UCBT. After UCBT, 15 patients had detectable serum BKV DNA, median 2.6×104 copies/ml (range, 2.5×102–7.9×106) with a median time to viremia of 40 days (range, 26–733). The cumulative probability of developing BK viremia by day 100 was 0.52 (95% CI, 0.33–0.71). In 9 of the 15 patients with detectable serum BKV DNA, urinary BKV PCR was also performed. All 9 tested patients had detectable urinary BKV and developed clinical symptoms ranging from dysuria to hemorrhagic cystitis. To determine whether development of BK viremia was related to the immunological status, we analyzed detection of serum BKV DNA in conjunction with parameters of immune reconstitution. At 6 and 12 months after transplantation development of BK viremia displayed a statistically significant inverse correlation with CD4+ and CD8+ T cells (p<0.05). Development of BK viremia at these time intervals also inversely correlated with CD4+CD45RO+ and CD8+CD45RO+ T cells (p<0.05), consistent with a potentially significant role of these effector populations in preventing and/or clearing BKV. Conversely, simultaneoulsy, there was a significant positive correlation of BK viremia with T regulatory cell numbers (p<0.05) suggesting that cellular mechanisms of Treg-mediated immune suppression were directly involved in regulating this clinical outcome. At 3 months after UCBT there was a significant positive correlation (p<0.05) between BK viremia and T cell receptor excision circles (TRECs), which are expressed in recent thymic emigrant T cells. BK viremia was not dependent on any other immune cell populations including CD20+ B cells, CD16+CD56+ NK cells and CD14+ monocytes. Furthermore, prevention and/or clearance of BK viremia was not dependent on naïve cell numbers as determined by lack of correlation between BK viremia -or absence thereof- with CD4+CD45RA+ T cells and CD8+CD45RA+ T cells. These observations were in complete contrast to our previous findings regarding CMV-specific immunity, which revealed that prevention and/or clearance of CMV viremia depend on reconstitution of thymopoiesis and increase of TRECs and naïve CD4+CD45RA+ cells. In addition, we found no correlation between development of CMV viremia and BK viremia in UCBT recipients. Our results indicate that reactivation of BK virus occurs with high frequency in adult UCBT recipients and is related to the inability of TREC positive cells to control BK viremia, the impaired and delayed reconstitution of CD4+ and CD8+ T effector cells, and the suppressive function of Treg. Furthermore, our results indicate that distinct immunological mechanisms govern CMV-specific and BK-specific anti-viral responses after UCBT.

Disclosures:
No relevant conflicts of interest to declare.