Hematopoietic Stem Cell Transplantation Restores Naïve T-Cell Populations in Atm-Deficient Mice and in Preemptively Treated Patients With Ataxia-Telangiectasia

Abstract

Background: Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer susceptibility. Cellular immunodeficiency is based on naïve CD4⁺ and CD8⁺ T-cell lymphopenia. Hematopoietic stem cell transplantation (HSCT) offers a potential to cure immunodeficiency and cancer due to restoration of the lymphopoietic system. The aim of this investigation was to analyze the effect of HSCT on naïve CD4⁺ as well as CD8⁺ T-cell numbers in A-T. Methods: We analyzed total numbers of peripheral naïve (CD45RA⁺CD62L⁺) and memory (CD45RO⁺CD62L^-) CD4⁺ and CD8⁺ T-cells of 32 A-T patients. Naïve (CD62L^highCD44^low) and memory (CD62L^lowCD44^high) T-cells were also measured in Atm-deficient mice before and after HSCT with GFP-expressing bone marrow derived hematopoietic stem cells. In addition, we analyzed T-cells in the peripheral blood of two A-T patients after HLA-identic allogeneic HSCT. Results: Like in humans, naïve CD4⁺ as well as naïve CD8⁺ lymphocytes were decreased in Atm-deficient mice. HSCT significantly inhibited thymic lymphomas and increased survival time in these animals. Donor cell chimerism increased up to more than 50% 6 months after HSCT accompanied by a significant increase of naïve CD4 and CD8 T-cell subpopulations, but not of memory T-cells. This finding was also identified in the blood of the A-T patients after HSCT. Conclusion: HSCT seems to be a feasible strategy to overcome immunodeficiency and might be a conceivable strategy to avoid T-cell driven cancer in A-T at higher risk for malignancy. Naïve CD4 and CD8 T-cells counts are suitable markers for monitoring immune reconstitution post-HSCT. However, risks and benefits of HSCT in A-T have to be properly weighted.

Keywords: ATM; CD45RA naïve lymphocytes; ataxia telangiectasia; immune deficiency; stem cell transplantation.

Figure 1

Cellular immune constitution in patients with Ataxia Telangiectasia compared to healthy controls. Blood samples of 32 A-T patients (colored dots) were analyzed for total numbers of (A) naïve CD4 T-cells (CD4⁺/CD45RA⁺CD62L⁺), (B) central memory CD4 T-cells (CD4⁺/CD45RO⁺CD62L⁺), (C) naïve CD8 T-cells (CD8⁺/CD45RA⁺CD62L⁺), and (D) central memory CD8 T-cells (CD8⁺/CD45RO⁺CD62L⁺) in comparison to healthy sex- and age-matched controls (black dots, n = 20). Black line and black dashed lines represents the 50th, the 5th and 95th percentile of the standard values, respectively.

Figure 2

Cellular immune constitution in Atm-deficient mice compared to wildtype mice. Total numbers of lymphocytes (A), CD3⁺ T-cells (B), CD19⁺ B-cells (C), NKp46⁺ natural killer cells (D), CD4⁺ T-cells (E), CD4⁺/CD62L^highCD44^low (F), CD4⁺/CD62L^highCD44^high (G), CD4⁺/CD62L^lowCD44^high (H), CD8⁺ T-cells (I), CD8⁺/CD62L^highCD44^low (J), CD8⁺/CD62L^highCD44^high (K), CD8⁺/CD62L^lowCD44^high (L) in the blood of 8–10 week-old Atm-deficient mice (n = 14) compared to wild-type mice were analyzed (n = 8). Data are presented as mean ± SEM.

Figure 3

Survival and chimerism in Atm-deficient mice after syngeneic hematopoietic SCT. Survival curves showed as Kaplan-Meier plots derived from Atm^−/− mice, after syngeneic HSCT (A). Total numbers of lymphocytes (B), CD3⁺ T-cells (C), CD3⁺/CD4⁺ helper T cells (D), CD3⁺/CD8⁺ cytotoxic T-cells (E), CD4⁺/CD62L^highCD44^low (F), CD4⁺/CD62L^lowCD44^high (G), CD8⁺/CD62L^highCD44^low (H), and CD8⁺/CD62L^lowCD44^high (I) in blood sample of untreated Atm^−/− mice (n = 15), syngeneic transplanted Atm^−/− mice (n = 11) compared to untreated Atm^+/+ mice (n = 12). Data are presented as mean ± SEM.

Figure 4

Restoration of immune reconstitution in an A-T patient post-HSCT. Total numbers of lymphocytes (A), CD3⁺ (B), CD3⁺/CD4⁺ (C), CD3⁺/CD8⁺ (D), naïve CD45RA CD4⁺ and CD8⁺ phenotype (E,G) and memory CD45RO CD4⁺ and CD8⁺ phenotype (F,H). Samples were collected from two A-T patients 1 and 2 years after HLA-identical HSCT.