Immune monitoring in humans after manipulation by B cell depletion and immunization
Author: Vallerskog, Therese
Date: 2007-02-02
Location: Föreläsningssalen vid Centrum för Molekylär Medicin (CMM, L8:00), Karolinska Universitetssjukhuset
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
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thesis.pdf (792.5Kb)
Abstract
The overall goal of this thesis was to study the influence of
immunomodulatory drugs on the human immune system. The approach was
bi-directional; ex vivo studies were performed after B cell depletion
with rituximab treatment in patients with SLE and RA, and an in vivo
assay was established to study effects of drugs on immune responsiveness.
To study immunological consequences of B cell depletion by rituximab in
treatment resistant patients with SLE and RA we collected blood samples
before and after treatment. Our analysis was focused on time points
related to absence and return of B cells after depletion. In patients
with SLE, changes of cellular phenotypes were analyzed by flow cytometry
and changes in antibody levels in serum by ELISA. We observed an increase
of activated T cells as well as an increase of regulatory T cells after B
cell depletion. There was a selective decrease of antibodies in serum.
IgM and IgE decreased rapidly after B cells depletion as well as the
disease activity associated autoantibodies against dsDNA and C1q. BAFF
and APRIL levels were measured by ELISA in serum of both SLE and RA
patients. Levels of BAFF increased in all patients after rituximab
therapy. In patients with SLE, the levels of APRIL decreased after B cell
depletion, and in patients with RA we observed heterogeneous changes.
To set up an assay to measure individual immune responsiveness, we used
immunizations as a tool to trigger an immune response. Healthy volunteers
were immunized with four weeks interval with either influenza vaccine,
three or four times (n=11) or with tetanus toxoid four times (n=7). Blood
samples were collected before and at four occasions between days 4 to 10
after each immunization. Humoral immunity to the influenza vaccine and
tetanus toxoid was measured by ELISPOT (circulating B cells) and ELISA
(antibodies). Cellular reactivity to the influenza vaccine was measured
by FASCIA (proliferation) and Bio-Plex suspension array system
(cytokines). Comparing the response to influenza and tetanus, the first
immunization with influenza vaccine resulted in ten times more B cells
secreting antigen-specific antibodies compared to immunization with
tetanus toxoid. The second and third influenza immunizations induced
comparable B cell immune responses, while there was a very low or no
response to tetanus toxoid. Antibody titers and T cell responses only
increased significantly after the first immunization. Thus measuring B
cell responses by ELISPOT to repeated immunizations with influenza
vaccine provide a method to evaluate immune responsiveness. Tetanus
toxoid was not a suitable antigen trigger for such studies.
In conclusion, we observed an effect on both the humoral and the cellular
immune systems after rituximab-induced B cell depletion in patients with
SLE. Further on, levels of BAFF increased after the therapy in patients
with SLE and RA, while APRIL decreased in SLE only. We have set up an
assay in which reproducible immune responses can be measured after
immunization 2 and 3 with influenza vaccine. Such an assay allows us in
the future to estimate the influence of immunomodulatory drugs on the
immune responsiveness in single patients.
List of papers:
I. Vallerskog T, Gunnarsson I, Widhe M, Risselada A, Klareskog L, van Vollenhoven R, Malmstrom V, Trollmo C. (2007). "Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE." Clin Immunol 122(1): 62-74
Pubmed
II. Vallerskog T, Heimburger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, Malmstrom V. (2006). "Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis." Arthritis Res Ther 8(6): R167
Pubmed
III. Vallerskog T, Gaines H, Feldman A, Culbert E, Klareskog L, Malmström V, Trollmo C. (2007). "Serial re-challenge with influenza vaccine as a tool to study individual immune responses." (Manuscript)
IV. Vallerskog T, Klareskog L, Culbert E, Trollmo C. (2007). "Multiple immunizations with tetanus toxoid are not suitable to measure reproducible immune responsiveness." (Manuscript)
I. Vallerskog T, Gunnarsson I, Widhe M, Risselada A, Klareskog L, van Vollenhoven R, Malmstrom V, Trollmo C. (2007). "Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE." Clin Immunol 122(1): 62-74
Pubmed
II. Vallerskog T, Heimburger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, Malmstrom V. (2006). "Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis." Arthritis Res Ther 8(6): R167
Pubmed
III. Vallerskog T, Gaines H, Feldman A, Culbert E, Klareskog L, Malmström V, Trollmo C. (2007). "Serial re-challenge with influenza vaccine as a tool to study individual immune responses." (Manuscript)
IV. Vallerskog T, Klareskog L, Culbert E, Trollmo C. (2007). "Multiple immunizations with tetanus toxoid are not suitable to measure reproducible immune responsiveness." (Manuscript)
Issue date: 2007-01-12
Rights:
Publication year: 2007
ISBN: 978-91-7357-061-9
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