Altered immune reconstitution of B and T cells precedes the onset of clinical symptoms of chronic graft-versus-host disease and is influenced by the type of onset

Abstract

We analyzed lymphocyte subpopulations and cytokines 3 months after allogeneic hematopoietic stem cell transplantation aiming to identify predictive cellular and serum markers for chronic graft-versus-host disease (cGVHD). Samples of 49 patients (pts) (no cGVHD (n = 14), subsequent quiescent onset (n = 16), de novo onset of cGVHD (n = 19)) were analyzed in the absence of active GVHD by flow cytometry and enzyme-linked immunosorbent assay. All mean absolute cell counts are presented as cells per microliter; relative cell counts are presented as percentage of lymphocytes. Pts with subsequent de novo cGVHD had significantly higher relative and absolute counts of CD4+ T cells including higher absolute counts of CD4+ memory T cells (22.36%; 206.55/μl; 136/μl, respectively) compared to pts with subsequent quiescent onset of cGVHD (12.41%; 83.42/μl; 54.3/μl) and pts without cGVHD (10.55%) with regard to relative counts of CD4+ T cells. Similarly, significantly more relative and absolute regulatory T cell numbers (CD4+FOXP3+) were detected in pts with de novo onset of cGVHD (3.08% and 24.63/μl) compared to those in pts without (1.25% and 9.06/μl) or with quiescent onset of cGVHD (1.15% and 6.91/μl). Finally, relative B cell counts, including naïve and memory B cells, were also significantly decreased in pts developing quiescent cGVHD (0.85, 0.73, 0.12% resp.) when compared to pts with de novo onset (5.61, 5.24, 0.38%). The results demonstrate that alterations in immune reconstitution are already present before onset of clinical symptoms and differ between de novo and quiescent onset of disease.

Role of B cells in chronic graft‐versus‐host disease after allogeneic stem cell transplantation in children and adolescents

“…A similar pattern was observed for the total CD4 + T‐helper subset, however, the latter was higher during the first 100 days in children later developing cGvHD (Fig A). This phenomenon has also been described in adult patients (Bohmann et al , ) and suggests a peculiar role of CD4 + T‐helper cells in human cGvHD aetiology. No significant differences were observed for CD8 + cytotoxic, CD4 + memory T‐, and natural killer cells (data not shown), probably related to the higher proliferation and differentiation potential of CD8 + and memory T cells under homeostatic conditions.…”

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

“…30 B cells exhibit significant abnormalities during immune reconstitution including aberrant B-cell activation, reduced frequency of regulatory B cells, and higher proportion of memory B cells. [31][32][33][34] Antibodies against both alloantigens and autoantigens are often detected after HSCT and deposition of alloantibodies on target tissues leads to the development of cGVHD in mouse models. 11,15,17,19,35 Therapies that target B cells, such as anti-CD20 antibody rituximab and Bruton tyrosine kinase inhibitor ibrutinib, have proven to be effective in mouse models and clinically beneficial in human trials.…”

Developing role of B cells in the pathogenesis and treatment of chronic GVHD

“…The latest opinions state that cGVHD onset is a consequence of altered immune reconstitution by lymphocytes (Bohmann et al , ). T‐lymphocyte subset monitoring is conventional after HSCT, while B‐cell subset monitoring is not.…”