Antibody responses to vaccination and immune function in patients with haematological malignancies - studies in patients with chronic lymphocytic leukaemia autologous stem cell recipients

Abstract

This thesis concerns the antibody responses to vaccination and immune function of patients with several forms of haematological diseases. Antibody responses in patients with chronic lymphocytic leukaemia (CLL) and in autologous stem cell transplant recipients were studied. In the autologous stem cell transplantation (aSCT) group, immune reconstitution after aSCT was analysed in detail during 15 months following transplantation. The first part of the thesis concerns patients with chronic lymphocytic leukaemia (CLL). Antibody responses to single and booster vaccination with influenza virus vaccine in patients with CLL are described. In these patients, antibody responses to a single vaccination with influenza virus vaccine were severely impaired with only limited improvement after booster vaccination. Next, antibody responses to vaccination with tetanus toxoid (TT) conjugated Haemophilus influenzae type b (Hib) vaccine and a non-conjugated 23-valent pneumococcal polysaccharide vaccine in CLL patients with and without ranitidine treatment are presented. In patients treated with ranitidine, post-vaccination anti-Hib and anti-TT antibody titres were higher as in CLL patients without ranitidine treatment. No beneficial effect of ranitidine on anti-pneumococcal antibody titres was found. The second part of the thesis concerns patients who underwent autologous stem cell transplantation (aSCT). The immune response to vaccination and development of immune function after aSCT were studied. Patients were vaccinated with Hib vaccine at 6, 8 and 14 months after aSCT. The vaccination schedule resulted in adequate antibody response rates and functional maturation of anti-Hib antibodies (measured by antibody avidity and phagocytosis of antibody coated Hib bacteria by granulocytes). In order to evaluate the antibody response to vaccination in the context of the cellular immune reconstitution, we determined peripheral blood lymphocyte subsets and function in aSCT patients. Natural killer cells and total number of T lymphocytes normalised early after aSCT, whereas B lymphocytes and subsets of T lymphocytes (especially CD4+ and CD45RA+ cells) remained low during a longer period. We analysed the correlation between lymphocyte subsets and antibody responses and found a relation between CD19+ cell counts and anti-Hib antibody responses. A minimum threshold level of ≥ 0.20x109/L CD19+ cells appears to be required for adequate responses to vaccination. Furthermore, the functional reconstitution of cellular immunity of the patients was assessed by determination of in vitro T-cell proliferation and cytokine production. T-cell proliferation significantly increased from 6 to 15 months after transplantation. Levels of T helper 1 (Th1) cytokines IFN-g and TNF-a were strikingly lower in patients compared to healthy controls, whereas at 15 months post-transplantation, levels of T helper 2 (Th2) cytokines IL-5 and IL-13 were significantly higher in post-transplantation patients compared to controls. The adequate production of Th2 cytokines fits with the observed adequate in vivo antibody responses after vaccination, whereas the subnormal production of Th1 cytokines might contribute to the relatively high occurrence of viral infections after aSCT. Finally, various aspects of infection prevention in patients with CLL and after aSCT in addition to the implications of this research for general practice are discussed