Evaluation of Human Polyomavirus (BKV)–Specific T Cell Immune Reconstitution in Allogeneic Haematopoietic Stem Cell Transplant Recipients,

Abstract 3223

Abstract

The human polyomavirus type 1, better known as “BK virus” (BKV), persists in a latent state in more than 90% of the world's population. It is infamous as a pathogen in kidney transplant recipients by causing BKV-associated nephropathy (BKVN) often resulting in allograft dysfunction and loss. BKV has also been associated with hemorrhagic cystitis (HC) in haematopoietic stem cell transplant (HSCT) recipients. However, treatment for this condition remains challenging, as the mechanism through which BKV reactivation causes HC in HSCT recipients is not known. In addition, there is currently little data about the reconstitution of BKV-specific immunity after HSCT and its relationship to HC. It is still unclear whether the BKV-specific T cell response helps to prevent and bring about the resolution of HC, or if HC is an immunopathology and the BKV specific immunity damages the bladder mucosa in the process of attacking BKV-infected urothelial cells.

We hypothesized that BKV-associated HC is initiated by an imbalance between immune surveillance and BKV reactivation, followed by eventual rebound of BKV- specific T immunity causing an immunopathological reaction towards BKV-infected urothelial cells that ultimately lead to cystitis after HSCT. We aim to correlate BKV titre levels in the urine and blood with BKV- specific T cells. This is a novel prospective study that describes the immune reconstitution of BKV specific T cells immunity after allogeneic HSCT and uses the clinical manifestation of HC as a maker to analyze reconstitution of the immune system post HSCT.

This study was approved by the institutional review board. Ten patients undergoing allogeneic HSCT were recruited over a 1 year period. The clinical data collected included conditioning regime, indication for transplant, presence of GVHD and development of HC. Patient's blood samples were collected prior to conditioning and at 4 weekly intervals for 24 weeks. Peripheral blood mononuclear cells (PBMCs) isolated from these whole blood samples were then stimulated with overlapping peptide mixes of BK LT and VP1. Quantification of BKV-specific T cells were accomplished by flow cytometry.

Results revealed higher levels of CD3+IL-17+BKV specific T cells (p<0.05) in subjects who developed HC compared to those who did not. Peak levels of CD3+IL-17+BKV specific T cells were observed just before or just after the presentation of HC. Both CD4+IL-17+ (p<0.01) and CD8+IL-17+ (p=0.05) BKV specific T cells were significantly higher in patients who developed HC compared to those who did not. This increment of IL-17+ BKV-specific T immune cells coincided with high levels of BKV detected in the urine.

These preliminary results strongly suggest that BKV-associated HC is an immunopathology caused by IL-17 secreting BKV-specific T cells. Though our cohort of patients is small however in view of the promising results; we plan to extend the study to a larger cohort of patient. The demonstration of an immunological basis of HC will provide a theoretical framework for the development of potential immunotherapeutic interventions in the prevention and treatment of HC.