Cytomegalovirus Drives Mixed Chimerism Following T-Cell Depleted Allogeneic HSCT, Providing Protective Immunity In The Absence Of GvHD
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A number of factors influence the incidence and degree of T-cell mixed chimerism following allogeneic stem cell transplantation (HSCT). The most well-recognized of these include donor source, GvHD and T-cell depletion of the graft. We hypothesized that in the ‘pro-tolerogenic’ environment following T-cell-depleted reduced intensity HSCT, viral infection could drive differential expansion of donor or recipient memory T cell (Tmem) populations, contributing to differences in the degree of mixed chimerism. Viral infection, more specifically cytomegalovirus (CMV) infection, has been shown to drive pauci-clonal T cell expansions in the early post-HSCT period, skewing T-cell repertoire reconstitution. Since CMV infection is associated with maintenance of relatively large memory T cell pools, and viral ‘reactivation’ can be associated with very large expansions of virus-specific T cells, we predicted that recipient T-cell chimerism would be greater following recipient seropositive/ donor seronegative (R+/D-) versus recipient seronegative/ donor seropositive (R-/D+) HSCT due to differential expansion of virus-specific Tmem. We evaluated the outcomes of 46 consecutive reduced intensity transplants incorporating in vivo alemtuzumab, in which these CMV serostatus combinations were present. Recipient chimerism was markedly greater in the R+/D- cohort (median 50% recipient, range 0-95% versus median 4%, range 0-95% respectively, P = 0.0044), and the correlation was greater when analysis was restricted to those with sibling donors (n=34, median 68% (2-95%) recipient versus 4% (0-95%) respectively, P = 0.0018), or to patients without grade II-IV acute or extensive chronic GvHD (n=33, median 63% (2-95%) recipient versus 2% (0-70%) respectively, P = 0.0019). At 6+ months post transplant, CMV-specific T cells accounted for 0.4-24% of the CD8+ T cell compartment. All such virus-specific T cells in R+/D- patients were recipient-derived, as demonstrated by chimerism analyses of CMV pp65-, pp50- or IE-1-specific HLA-streptamer-selected CD8+ T cells. Furthermore, chimerism was consistently more skewed towards recipient in the CD8+ as opposed to the CD4+ T cell compartment, in keeping with larger clonal burst sizes of CD8+ versus CD4+ virus-specific T cells. Since the majority of recipient-derived T cells were not CMV-specific, we hypothesize that events early post-transplant might have a role in ‘imprinting’ the level of recipient chimerism, which thereafter remains stable in the absence of GvHD. Interestingly, these recipient-derived CMV-specific T cells conferred apparent protection against multiple CMV reactivation episodes. The number of reactivation episodes and number of days on treatment within the R+/D- cohort were significantly higher for those with <10% (n=9) versus those with >10% (n=16) recipient chimerism (median 3 (range 1-10) versus 1 (1-3), P = 0.0044, and median 88 days (19-412) versus 21 days (17-63), P = 0.001, respectively). R+/D- transplants were not, therefore, generally associated with recurrent problematic CMV infection. Indeed, this scenario was largely confined to the group of patients developing GvHD, who suffered both from reduced absolute lymphocyte counts secondary to corticosteroids, and eradication of the recipient-derived T cell compartment including the CMV-specific Tmem pool. Paradoxically, this suggests that T-cell depletion may actually reduce the incidence of problematic CMV infection in this ‘high-risk’ group by facilitating persistence of recipient CMV-specific T cells. Twelve R+/D- patients received donor-lymphocytes at later time points for persistent recipient chimerism (median 78% recipient (5-95%)). All converted to<5% recipient (median 0%). Serial analysis revealed rapid priming of donor-derived CMV-specific immunity in the absence of quantifiable CMV viremia (PCR became positive below the limit of quantification), with expansion of CMV-specific T cells accounting for up to 41% of the CD8+ compartment. In conclusion, these data indicate that in the absence of GvHD, CMV influences the pattern of chimerism following T cell depleted transplants, that recipient virus-specific T cells provide protection from recurrent CMV reactivation, and that conversion to donor chimerism following donor-lymphocytes is associated with clinically silent transition to donor-derived immunity.
