Interplay of Cellular and Humoral Immune Responses against BK Virus in Kidney Transplant Recipients with Polyomavirus Nephropathy

Abstract

Reactivation of the polyomavirus BK (BKV) causes polyomavirus nephropathy (PVN) in kidney transplant(KTx) recipients and may lead to loss of the renal allograft. We have identified two HLA-A*0201-restricted nine-amino-acid cytotoxic T lymphocyte (CTL) epitopes of the BKV major capsid protein VP1, VP1 p44 , and VP1 p108. Using tetramer staining assays, we showed that these epitopes were recognized by CTLs in 8 of 10 (VP1 p44 ) and 5 of 10 (VP1 p108 ) HLA-A*0201 ؉ healthy individuals, while both epitopes elicited a CTL response in 10 of 10 KTx recipients with biopsy-proven PVN, although at variable levels. After in vitro stimulation with the respective peptides, CTLs directed against VP1 p44 were more abundant than against VP1 p108 in most healthy individuals, while the converse was true in KTx recipients with PVN, suggesting a shift in epitope immunodominance in the setting of active BKV infection. A strong CTL response in KTx recipients with PVN appeared to be associated with decreased BK viral load in blood and urine and low anti-BKV antibody titers, while a low or undetectable CTL response correlated with viral persistence and high anti-BKV antibody titers. These results suggest that this cellular immune response is present in most BKV-seropositive healthy individuals and plays an important role in the containment of BKV in KTx recipients with PVN. Interestingly, the BKV CTL epitopes bear striking homology with the recently described CTL epitopes of the other human polyomavirus JC (JCV), JCV VP1 p36 and VP1 p100 . A high degree of epitope cross-recognition was present between BKV and corresponding JCV-specific CTLs, which indicates that the same population of cells is functionally effective against these two closely related viruses.BK virus (BKV) is the etiologic agent of polyomavirus nephropathy (PVN), an infection of the kidney occurring in up to 8% of kidney transplant (KTx) recipients (38). BKV infects 90% of adults (20) but does not cause any disease in healthy individuals. Viral reactivation in renal transplant recipients occurs in the setting of pharmacologic immunosuppression. This reactivation leads to a lytic infection of renal tubular epithelial cells of the transplanted kidney, which was responsible for renal allograft loss in as high as 45 to 67% of cases in early experiences and is currently responsible for 10 to 30% of renal allograft losses (29,35,38). There is no specific antiviral treatment for PVN. Therefore, this disease is a growing medical problem as the population of KTx recipients continues to increase. The only currently available therapeutic option for PVN consists of reduction of chemical immunosuppression, which allows reconstitution of the immune system to clear the virus (4) but which may also be associated with an increased risk of transplant rejection. Hence, prognostic markers of disease evolution and a better understanding of the immune response against BKV are urgently needed for the appropriate management of patients with PVN.BKV has 75% homology with JC virus (JCV), the cau...

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

“…11,13 After initial infection, BKV remains latent in the kidney urothelium and can reactivate with immunosuppression to cause disease, such as BKV-associated nephropathy in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant patients. 11,14,15 BKV reactivation has also been observed in immunocompetent individuals, with urinary viral shedding occurring in about 5% of individuals, 16 although no disease process has yet been associated with BKV reactivation in immunocompetent individuals.…”

Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

“…Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in PBMCs in patients with viruria could provide some insight into viral replication. The mechanisms involved appear to be quite specific for JC virus, since we found in our study that BK virus, which also resides in the kidney and shares epitopes with JC virus that are recognized by the same population of cytotoxic T cells, 26,36 showed no sign of reactivation either in blood or in urine.…”

“…[26][27][28] The lower limit of detection for either virus was 10 copies per microgram of cellular DNA in PBMC samples and 25 copies per milliliter in plasma or urine samples.…”

“…Quantitative real-time polymerase-chain reaction (PCR) was used to measure BK virus DNA 26 and JC virus DNA 27 in urine, plasma, and peripheral-blood mononuclear cells (PBMCs), as described previously. [26][27][28] The lower limit of detection for either virus was 10 copies per microgram of cellular DNA in PBMC samples and 25 copies per milliliter in plasma or urine samples.…”

Intragraft Blood Dendritic Cell Antigen-1–Positive Myeloid Dendritic Cells Increase during BK Polyomavirus–Associated Nephropathy

“…One can hypothesize that mDCs orchestrate the immune response during BKPyVAN or that the influx of mDCs is a bystander effect of tubulointerstitial inflammation in these patients; however, we did not observe BDCA-1 + mDCs in areas of tubulitis during TCMR. Thus far, most studies reported deficiencies of all DC subtypes in the peripheral blood during BKPyVAN, 16,20,21 whereas increased amounts of all DC subtypes have been reported in renal biopsies during acute rejection. 22 However, the number of intragraft DCs in BKPyVAN has not been studied before.…”