Long-term immune reconstitution after autologous stem-cell transplantation for severe autoimmune diseases

Objectives

We performed a detailed analysis of the newly developing immune system in patients treated with autologous stem-cell transplantation (ASCT) for severe autoimmune diseases with special respect to the origin and the kinetics of repopulating B-cell and T-cell subsets in correlation to the clinical response.

Methods

Peripheral blood lymphocytes were analyzed using multiparameter flow cytometry, including monitoring of the TCR-Vbeta repertoire on CD4⁺ Th cells. Thymic activity was determined assessing absolute counts of peripheral blood CD31⁺ thymic naive Th cells.

Patients and results

Thirteen patients with a median follow-up of 54 months have so far been included in the trial: polychonditis (n = 1), systemic lupus erythematosus (SLE) (n = 6), systemic sclerosis (SSc) (n = 3), panniculitis (n = 1) and multiple sclerosis (n = 2). Clinical remission has been achieved in all patients with polychondritis (n = 1), SLE (n = 6) and multiple sclerosis (n = 2) whereas we observed progression of disease in all patients with SSc (n = 3) and panniculits (n = 1). One SLE patient relapsed after being free of any clinical and serological symptoms for 17 months.

T-lymphocyte compartments reconstituted functionally in all patients, indicated by the reappearance and persistence of CD45RA⁺CD31⁺ thymic naive Th cells in high numbers with high levels of T-cell receptor excision circles and restored diversity of the Th-cell-receptor repertoire. In terms of Th-cell memory no autoreactive Th cells could be detected in responding patients. Reconstituted B cells were primarily of naïve phenotype (IgD⁺CD27^-) in the first 12–18 months after ASCT. As a cellular marker for disease activity, frequencies of CD19⁺CD27⁺⁺CD20^- plasma blasts, elevated in SLE patients prior to ASCT, normalized after treatment in all patients. In case of the non-responding patients with SSc, autoantibody titers were not affected by treatment. However, no major differences in the pattern of lymphocyte reconstitution could be detected as compared with responding patients.

Conclusion

The newly developing immune system after immunoablative therapy could be characterized as 'juvenile' in all patients. However, in some patients the regeneration of a naive immune system alone seems not to be sufficient to regain self-tolerance. We conclude that both the resetting of central and peripheral tolerance and the efficient eradication of autoreactive lymphocytes seem to be a prerequisite for stable induction of remission.