In pediatric patients with life-threatening IEI, allogeneic HSCT has a good safety profile and is a curative treatment. The recovery and long-term survival of these patients depend heavily on the prompt reconstitution and restoration of a donor-derived immune system. The EBMT/ESID recommendations suggest a variety of RIC-HSCT treatment combinations in this setting (15). In recent studies, researchers improved the outcomes, reaching overall survival (OS) rates of 75 to 80 percent for patients with different IEI (14, 16, 17). Throughout the past few years, we have consistently administered the same Flu-based RIC-HSCT to patients diagnosed with IEI (9, 16, 18). This paper reports the immune recovery of 41 IEI patients who received Flu-based RIC-HSCT. Some studies have shown that busulfan-based regimens have a slight advantage over Flu-based RIC regimens in achieving good donor chimerism, stable immune reconstitution, and long-term survival (14, 17). However, we show that the fludarabine/melphalan conditioning regimen provides long-term engraftment with low toxicity despite mixed chimerism in a quarter of the patients.
We also examined the predictors of recovery of lymphocyte subsets after transplantation. T cell reconstitution depends on the initial peripheral expansion of donor-derived memory T cells followed by thymus-dependent stem cell maturation and production of diverse T cell repertoire (19). Previous studies have shown that immune reconstitution after transplantation is influenced by several factors, including recipient age, stem cell source, conditioning regimens, donor-recipient HLA differences, CMV serostatus, and GVHD development (19–22). The results presented in this study indicated that total CD3+ and CD8+ T cell counts returned to normal within 6 to 9 months after HSCT in most patients; however, CD4+ T cells showed slow and poor recovery during follow-up. Although about two-thirds of the patients never achieved normal CD4 + T-cell counts, this delayed and incomplete CD4+ T-cell recovery did not translate into increased post-transplant infections during follow-up. Delayed CD4+ recovery also led to an inverse CD4+/CD8+ ratio. These results support previous suggestions that CD8+ T cells are reconstituted more rapidly than CD4+ T cells (23, 24). Peripheral T cell expansion of mature cells from grafts is primarily driven by rapid CD8+ T cell renewal (25). Compared to CD8+ T cells, CD4+ T cells appear more sensitive to ATG (26). Other factors affecting CD4+ T cell reconstitution were pre-transplant CMV infection and the development of cGVHD. These results are consistent with another study that examined immune reconstitution after HSCT and showed that CMV reactivation and cGVHD are significant determinants of immune reconstitution one year after HSCT (27). Previous studies have revealed the influence of CMV serological status and titers on immune reconstitution patterns after transplantation (28, 29). T-cell counts (CD4+ and CD8+) were significantly lower in recipients with high CMV titers (> 20,000 copies/ml) three months after HSCT (30). Acute GVHD and cGVHD have been documented to impair thymopoiesis, prevent normal T-cell renewal, and delay T-cell recovery patterns (31–33).
Achieving high donor chimerism typically leads to better outcomes and improved quality of life in transplanted IEI patients (14, 34). Furthermore, RIC regimens are generally associated with a predominance of mixed donor chimerism (16, 17). Our study demonstrated improved recovery kinetics of CD8+ T cells in the presence of full donor chimerism.
B-cell recovery after HSCT is variable and influenced by various factors such as stem cell source and use of ATG (11, 24, 35, 36). In our series, B cell reconstitution occurred during follow-up in about 85% of the patients, and the development of aGVHD significantly impacted the B cell recovery. Consistent with other studies, NK cells were the first lymphocytes to normalize, regardless of other factors (24).
In conclusion, although our study includes a relatively large number of patients using the same stem cell source and conditioning protocol, it is limited by its retrospective nature and the underlying heterogeneity of the IEI. Another limitation of our study is the unavailability of thymopoiesis evaluation and humeral and cellular functional assessments.
However, the results are conclusive in demonstrating important factors influencing lymphocyte subset recovery after PBSC transplant. Using an appropriate GVHD prophylaxis regimen and adequate treatment of CMV may improve the immune reconstitution post-HSCT