Essential Role of the Thymus to Reconstitute Naive (CD45RA+) T-Helper Cells After Human Allogeneic Bone Marrow Transplantation

Abstract

To contribute to the understanding of the role of the thymus in humans in the reconstitution of naive (CD45RA+) T cells after bone marrow transplantation (BMT), we compared T-cell regeneration in a unique situation, namely a thymectomized cancer patient (15 years old), with that of thymus-bearing patients after allogeneic BMT. These cases shared features of transplantation (total body irradiation, HLA-matched donors, and graft-versus-host disease prophylaxis with cyclosporine A) and all had an uncomplicated posttransplantation course. As shown by fluorescence-activated cell sorting analyses, the thymectomized host failed to reconstitute CD45RA+ T-helper cells even 24 months after BMT (11% CD45RA+ of CD4+ cells). In this patient, preferentially CD45RO+ cells contributed to the recovery of CD4+ cells (206 of 261/μL at 6 months and 463 of 558/μL at 24 months after BMT, CD45RA+ of CD4+ cells), whereas CD45RA+ cells remained low (<60/μL). In contrast, nine thymus-bearing hosts (5 children and 4 adults) examined between 6 and 24 months after BMT effectively reconstituted CD4+/CD45RA+ cells according to their normal age-related range (≥28% in adults and ≥50% in children). Five of these were analyzed sequentially at 6 and 9 months after BMT. Within this period, CD45RA+ cells increasingly contributed to the recovery of CD4+ cells (median, +21%), even when total CD4+ cells decreased. With respect to T-cytotoxic/suppressor cells, the thymectomized host retained the capacity to recover CD45RA+ cells (137 of 333/μL at 6 months and 596 of 1,046/μL at 24 months after BMT, CD45RA+ of CD8+ cells), a proportion similar to that seen in thymus-bearing hosts. These findings suggest that a thymus-independent pathway exists to regenerate CD45RA+ T-cytotoxic/suppressor cells, but residual thymus is essential to reconstitute naive (CD45RA+) T-helper cells after BMT in humans.

Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery

“…This is evidence of a thymus-independent pathway in CD8 + lymphocyte recovery. This hypothesis was supported by a patient who first underwent thymectomy and then allogeneic BMT: his CD8 + CD45RA + cell count remained within normal range post transplant (Heitger et al, 1997).…”

“…Ability to produce ÔnaiveÕ helper T cells (CD4 + CD45RA + ) decreases with age (Storek et al, 1995;Kook et al, 1996). T-cell recovery in children occurs partially via the thymic-dependent pathway (Mackall et al, 1993;Storek et al, 1995;Heitger et al, 1997), whereas strongly impaired restoration of ÔnaiveÕ helper T cells in adults usually results from thymic involution (Mackall et al, 1993), starting during the second decade od life (Small et al, 1999). Comparing our study groups (youngest cohort of patients < 5-year-old and the oldest one > 10 years), we observed statistically significant differences in the recovery of helper T cells (including ÔnaiveÕ CD45RA + cells) and B cells (including early B cells with co-statement of CD5 antigen) from 2 to 3 months to 1-1AE5 years post alloHCT.…”

“…Heitger et al (1997) wondered why CD8 + CD45RA + Ts cells expanded in parallel with CD4 + CD45RA + cells in their group of children. It is well known that CD8 + CD45RA + cells have the ability to regenerate without thymus abundance, independent of the patient's age (Mackall et al, 1993(Mackall et al, , 1995Heitger et al, 1997). What evidence is there that ÔnaiveÕ Th cells (CD4 + CD45RA + ) are considered to be thymus-dependent?…”

“…First, helper T cells (CD4 + ) express CD45RA + antigen when leaving the thymus (Pilarski et al, 1989). Second, there is no recovery of CD4 + CD45RA + lymphocytes over a long period of time in BMT recipients being deprived of thymus in comparison with those possessing this organ (Heitger et al, 1997). Third, ÔnaiveÕ helper T-cell reconstitution correlates with thymus size enlargement (Mackall et al, 1995;Mü ller et al, 1998).…”

A prospective analysis of the pattern of immune reconstitution in a paediatric cohort following transplantation of positively selected human leucocyte antigen‐disparate haematopoietic stem cells from parental donors

“…This pathway is generally referred to as peripheral expansion and predominates in the early phase following conventional bone marrow transplantation. This has been observed to be a persistent phenomenon in thymectomized hosts (Heitger et al, 1997) and in hosts with decreased thymic function, namely in adults or patients with intensive pretransplant chemotherapy (Mackall et al, 1995). Second, de novo maturation of naive T cells from bone marrow emigrants via passage through the thymus has been shown to occur after 6 months in children (Small et al, 1999).…”