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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
 
Ann Rheum Dis. Oct 2005; 64(10): 1397–1405.
Published online Apr 13, 2005. doi:  10.1136/ard.2004.033332
PMCID: PMC1755245
Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration
R Verburg, R Flierman, J Sont, F Ponchel, L van Dreunen, E Levarht, M Welling, R Toes, J Isaacs, and J M van Laar
Department of Rheumatology, Division of Nuclear Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.
Objective: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment.
Methods: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium.
Results: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p<0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes.
Conclusions: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.
Figure 1
Figure 1
 Synovial tissue taken from patient No 2 (table 1) before and 3 months after HDC + ASCT. Infiltration with numerous lymphocytes and plasma cells before stem cell transplantation, which were almost absent after the transplantation.
Figure 2
Figure 2
 Immunohistochemically stained synovial tissue in a responder with CD3, CD27, CD45RA, and CD45RO, before and 3 months after HDC + ASCT.
Figure 3
Figure 3
 Semiquantitative infiltration scores before, 3 months after, and 1 year after HDC + ASCT of responders and non-responders for CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO. *p<0.05, significant baseline difference between responders and (more ...)
Figure 4
Figure 4
 Co-expression of CD3 and CD45RO in RA synovial tissue before transplantation in a responder. CD3 (FITC = green) and CD45RO (TRITC = red) were detected using immunofluorescence techniques. (A) Rheumatoid synovial tissue showing CD3+ cell infiltrate. (more ...)
Figure 6
Figure 6
 The mean number of CD45RA, CD45RB, and CD45RO expressed as a percentage of CD3+cells. (A) Immunofluorescence double staining of peripheral blood mononuclear cells with CD3 plus CD45RA, CD45RB, or CD45RO in the five responders at screening and (more ...)
Figure 5
Figure 5
 Absolute cell count in peripheral blood mononuclear cells in the five responders for CD3, CD4, and CD8. Absolute cell numbers were calculated by multiplying absolute lymphocyte count (106/l (SEM)) by the percentage of each subset determined (more ...)
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