Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death.
We have studied the regeneration of T cell subsets and function after BMT in 21 children affected by combined immunodeficiency after BMT. In the first months, the striking predominance of CD4+ cells displayed the primed CD45R0+ phenotype and a high number of activated (HLA-DR+) T cells were observed. Regeneration of naive CD4+CD45RA+ cells correlated with the recovery of proliferative responses to mitogens (r = 0.64, P<0.001). Peripheral blood lymphocytes circulating after BMT undergo an increased process of in vitro cell death, resulting from two mechanisms: spontaneous apoptosis (SA), a consequence of defective production of IL-2 and down-regulation of Bcl-2 (P = 0.02 vs. healthy controls), and high susceptibility to activation-induced cell death (AICD) after restimulation with mitogens. In accordance with the role of CD95/Fas in this latter process, we have observed a high level of CD95 expression (P<0.001 vs. healthy controls), correlated with AICD (P<0.001) but not with SA, and decreasing with time after BMT (P<0.001). Both SA and AICD levels correlated with the presence of activated T cells and decreased with the progressive recovery of T cell proliferative response. Therefore, the lymphocyte hyperactivated status might explain their susceptibility to apoptosis and contribute to the genesis of immunodeficiency that follows BMT.
Brugnoni
D
D
Servizio di Immunologia Clinica, Spedali Civili and University of Brescia, Italy.
Airò
P
P
Pennacchio
M
M
Carella
G
G
Malagoli
A
A
Ugazio
A G
AG
Porta
F
F
Cattaneo
R
R
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D014181:Transplantation Immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology*
D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor