Early Thymus-Dependent Immune Reconstitution Following Αβ T Cells Depleted Haploidentical HSCT
Year: 2024
Type: article
Study design: Observational Study
Abstract: We have previously reported that the common lymphoid progenitor (CLP) content of grafts used in αβ T-cell/B-cell depleted haploidentical hematopoietic stem cell transplantation (αβhaplo-HSCT) was predictive of thymus-dependent immune reconstitution (CD4 T cell count) at Day 90 post transplant. However, since most viral infections occur prior to 90 days following HSCT, we now evaluated whether the CLP graft content correlated with the thymus-dependent immune reconstitution prior to Day 90. We evaluated 25 pediatric patients receiving αβhaplo-HSCT at Stanford Children's Health. Twenty-one patients had malignant (two relapse) and 4 non-malignant diseases. Nineteen recipients were pediatric, six were young adults and 14/25 received total body irradiation (TBI) while 11 receive reduced intensity regimes (RIC). The αβhaplo-HSCT grafts were G-CSF +/- Plerixafor mobilized peripheral blood stem cells and were immunophenotypically analyzed for CLP content by multicolor flow cytometry. CLP were defined as CD34+, Lin−, CD38+, CD127+. After αβhaplo-HSCT, recipient peripheral blood were analyzed for both frequency and absolute number of αβ T cells, their differentiation and the frequency of recent thymic emigrants (RTE). Naïve CD4 T cells were defined as CD3+, CD4+, CD45RA+, CD62L+; and RTE as CD45RA+, CD31+ cells gated on either total CD4 or naïve CD4 T cells. Naïve CD4 T cells were first detected on Day 30 in 8 patients (32%) then they increase over time. By Day 90, 22/25 recipients (88%) had detectable naïve CD4 T cells (Fig 1). To demonstrate that CD4 naïve T cells had differentiated in the recipient thymus, we analyzed the naïve cells using CD31, a marker of recent thymic differentiation. On Day 30, 90% of the naïve CD4 T cells were RTE and the frequency of RTE decreased with time. By Day 120 only 70% of the naïve CD4 T cells were RTE demonstrating that early RTE had lost CD31 expression but maintained their naïve immunophenotype (Fig2). The recipients with early development of naïve CD4 T cells were younger (Fig 3a), while the use of TBI had no impact (Fig 3b). We found no correlation between CLP in the graft and the early presence of CD4 RTE T cells. We have demostrated that naïve CD4 T cells can be detected as early as Day 30 post αβhaplo-HSCT, and that they defferentiate in the recipient thymus. With only two relapsed patients was not possible to determine whether early CD4 T cells immune reconstitution had any anti-leukemic effect. Studies on a larger cohort are underway to assess if the more rapid thymus dependent immune reconstitution results in a reduction in early viral reactivations or protection against relapse.
Institutions: Stanford Medicine, Stanford University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W4391599140