Long-Term Immune Reconstitution of Naive and Memory T Cell Pools after Haploidentical Hematopoietic Stem Cell Transplantation

Abstract

Haploidentical hematopoietic stem cell transplantation (HSCT) constitutes an important alternative for patients lacking a human leukocyte antigen (HLA)-matched donor. Although the use of haploidentical donors is increasingly common, the long-term impact of generating a donor-derived immune system in the context of an HLA-mismatched thymic environment remains poorly characterized. We performed an in-depth assessment of immune reconstitution in a group of haploidentical HSCT recipients 4 to 6 years posttransplantation, in parallel with the respective parental donors and age-matched healthy control subjects. Our data show that the proportion of naive and memory subsets in the recipients, both within CD8(+) and CD4(+) T cells, more closely resembled that observed in age-matched control subjects than in the donors. HSCT recipients displayed relatively high signal-joint T cell-receptor excision circle levels and a high frequency of the recent thymic emigrant-enriched CD31(+) subset within naive CD4(+) and naive regulatory T cells. Moreover, CD8(+), CD4(+), and regulatory T cells from HSCT recipients displayed a diverse T cell repertoire. These results support a key role for thymic output in T cell reconstitution. Nevertheless, HSCT recipients had significantly shorter telomeres within a naive-enriched CD4(+) T cell population than age-matched control subjects, despite the similar telomere length observed within the most differentiated CD8(+) and CD4(+) T cell subsets. Overall, our data suggest that long-term immune reconstitution was successfully achieved after haploidentical HSCT, a process that appears to have largely relied on de novo T cell production.

Improving Cytomegalovirus-Specific T Cell Reconstitution after Haploidentical Stem Cell Transplantation

“…In unmanipulated haplo-SCT, although the high T cell content of the graft potentially enhances the graft-versus-leukemia effect, recipients of unmanipulated grafts from alternative donors remain at risk of TRM for months/years after transplantation because of GVHD and its immunosuppressive treatments that antagonize T cell expansion and function. Delayed IR and increased risk of CMV infection remain critical problems early after transplantation, although long-term IR can successfully be achieved after haplo-SCT [74, 91]. …”

“…Increased thymic function might be responsible for better immune reconstitution in younger children [72], especially when compared with adult patients in whom naive thymic emigrants have been reported to appear in the circulation only 6 months after receipt of a T cell depleted HSCT [73]. Recently, Azevedo et al [74] investigated long-term IR after RIC based haplo-SCT with TCD, which followed by preemptive donor lymphocyte infusions (DLI). They found the proportion of naive and memory subsets in the recipients, both within CD8+ and CD4+ T cells, more closely resembled that observed in age-matched control subjects than in the donors.…”

“…They found the proportion of naive and memory subsets in the recipients, both within CD8+ and CD4+ T cells, more closely resembled that observed in age-matched control subjects than in the donors. Their data [74] suggested that long-term IR was successfully achieved after haploidentical HSCT, a process that appears to have largely relied on de novo T cell production. IR after haplo-SCT is usually slower than that after matched-sibling donor or matched-unrelated donor transplants [75]; however, the impact of HLA disparity on CMV-specific IR after haplo-SCT remains uncertain.…”

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Soon after transplant, most CMV-CTLs are of donor origin, while newly "educated" endogenous T cells from thymic output appear only later [86]. In haploidentical HSCT, early T-cell recovery is primarily based on peripheral expansion of naïve T cells and it appears delayed when compared with that of HSCT from HLA-identical siblings [87][88][89][90] Long-term immune reconstitution, however, mostly thymus-dependent, appears appropriate to maintain an adequate naïve T cell pool [91][92][93][94]. Adoptively transferred CMV-CTL can be detected long after HSCT and up to 2 years after infusion [95].…”

Engineering haploidentical transplants

“…25 Long-term T-cell recovery is largely dependent on de novo T-cell production mediated by thymopoeisis and more closely resembles that of age-matched controls rather than donor graft. 26 In this report, patients had robust and rapid immune reconstitution with nearly normal number of CD8+ and CD4+ central and effector memory T cells that were able to mount highly effective proliferative responses to PHA, tetanus, CMV and HSV as early as day +30 providing critical protection against infections, while the presence of large number of Tregs along with negligible numbers of naive CD45RA+ T cells may have contributed to the very low observed rate of GvHD. In the first 100 days post transplant, the phenotype of the reconstituting cells recapitulated the CD45RA-depleted graft content.…”