CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

Abstract

Key Points• CMV serostatus significantly influences chimerism levels after T-cell-depleted allogeneic transplantation.• CMV-specific T cells are exclusively of recipient origin after R1/D2 T-cell-depleted transplants and appear to provide protective immunity.Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R1)/seronegative donor (D2) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-celldepleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R1/D2 and R1/seropositive donor patients. We show that in R1/D2 patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R1/D2 setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity. (Blood. 2015;125(4):731-739)

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis

“…9 Specifically, subset analysis was performed on 446 adult patients with AML receiving PBSC grafts following a MA conditioning regimen without serotherapy and who received cyclosporine (CSA) and methotrexate (MTX)-based GVHD prophylaxis. In this subset analysis, CMV reactivation as a time-dependent covariate did not associate with decreased risk for relapse by 1 year (CMV reactivation: n 5 113, relapse 26% [95% CI, [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] vs no CMV reactivation: n 5 333, relapse 27% [95% CI, 22-32%]; P 5 .80). Likewise, D/R CMV serology itself did not associate with reduced risk for relapse (data not shown).…”

“…[25][26][27] Ironically, CMV-driven immunity by itself seems not to influence risk in leukemia relapse after HCT, but rather overall immune reconstitution in the allogeneic transplant recipient seems most important. 15 The current CIBMTR study performed a subset analysis on AML patients who received MA conditioning and PBSC grafts, as early CMV reactivation in this specific patient population has most often been reported to decrease AML relapse.…”

Cytomegalovirus Infection after CD34+-Selected Hematopoietic Cell Transplantation

“…A recent study in recipients of reduced-intensity conditioning HCT with grafts post- in-vivo TCD with alemtuzumab showed that R+/D− patients had fewer CMV related events and higher levels of recipient chimerism than R+/D+ recipients. Furthermore, CMV specific T-cells in R+/D− recipients were exclusively of recipient origin 23 . In our cohort, we also observed that R+/D+ patients had significantly higher CMV reactivation, numerically higher CMV persistent viremia, and worse one-year overall survival outcomes than R+/D− patients.…”

Herpesvirus infection following allogenic hematopoietic stem cell transplantation with TCRaβ and CD19 depletion: risk factors and outcome

“…Нами продемонстрировано, что пациенты со злокаче-ственными заболеваниями имеют более высокий риск реактивации ЦМВ-инфекции по сравнению с пациен-тами с незлокачественными заболеваниями, о чем свидетельствует результат мультивариантного ана-лиза. Этот факт частично объясняют опубликованные сообщения о роли персистирующих ЦМВ-специфиче-ских T-лимфоцитов реципиентов в контроле ЦМВ-ин-фекции после ТГСК [37]. Это предположение косвенно подтверждает большая частота смешанного химериз-ма в Т-клеточной фракции среди пациентов с незло-качественными заболеваниями из-за использования у них менее интенсивных режимов кондиционирова-ния и, вероятно, отсутствия лимфодеплетирующих блоков химиотерапии до ТГСК.…”

“…В моно-и мультива-риантных анализах получено значимое влияние на риск ЦМВ-виремии, предшествующей острой РТПХ > II стадии, серопозитивности реципиента до ТГСК и наличия у пациента злокачественного заболевания. КВ ЭБВ-инфекции -33% (95% ДИ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Фактором риска ЭБВ-виремии являлась острая РТПХ > II стадии.…”