Preservation of vaccine-induced long-term B cell memory and the effects of immunosuppressive treatment
Author: Ingelman-Sundberg, Hanna M
Date: 2015-02-13
Location: Leksell auditorium, Eugeniahemmet T3, plan 02, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Inst för kvinnors och barns hälsa / Dept of Women's and Children's Health
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Thesis (2.364Mb)
Abstract
Immune memory after vaccination is largely dependent on the combination of antibody production from long-lived plasma cells, and a supporting pool of antigen-primed memory B cells. It has been observed that individuals with certain immunosuppressive conditions or treatments have a weakened B cell memory, but the mechanisms behind remain elusive. The aim of this thesis was to evaluate B cell immunity in healthy children, and how HIV-1 infection, antineoplastic therapy, and rheumatic disease and treatment can impact on various features of B cell memory induction and maintenance.
In paper I, we explored the hyperactivation of B cells observed in patients carrying HIV-1 infection, and showed that it can be partly induced by ligation of soluble cleaved CD27 to CD70 on the surface of memory B cells. In paper II, we aimed at comparing the establishment of serum antibody titers and memory B cells after vaccination against measles and rubella in healthy children. We found that the memory B cell pool remained stable also early after vaccination, whereas the corresponding serum IgG titers decayed with time. In contrast, both the serum IgG levels and frequency of blood memory B cells in healthy young adults appeared stable. This implied that the antibody production and memory B cell compartment are two separate entities with independent regulation, and that it takes longer time to establish a stable pool of circulating antibodies. How these two parts of B cell memory are affected by immunosuppressive disease and treatment was addressed in papers III and IV. In paper III, we used a rhesus macaque model for high-dose Doxorubicin treatment, and concluded that the established vaccine-induced memory B cell pool was depleted, contrary to long-lived plasma cells and the resulting serum IgG titers. These observations supported the finding of independent regulation of the two B cell memory compartments, and revealed different sensitivity to chemotherapy. The bone marrow plasma cell niche was additionally studied in an in vitro model for plasma cell – stromal cell cross talk, where we discovered that in vivo relevant concentrations of Doxorubicin could hamper the output of pivotal survival factors from stromal cells. In paper IV, we examined memory B cells and circulating IgG titers in children with rheumatic disease, treated with low-dose Methotrexate and TNF-α inhibition. We noted that serum IgG titers against tetanus were lower in rheumatic patients than in healthy controls, and that patients who had only received one measles vaccine dose had lower levels of measles-specific memory B cells. This stresses the importance for children with rheumatic disease and treatment to follow the full vaccine schedule.
To summarize, this thesis has contributed to enhanced knowledge on how B cell memory is induced, preserved and at risk of disruption by common immune disorders and treatment. Hopefully, our findings can aid future improvement of functional vaccine regimes for immunocompromised children.
In paper I, we explored the hyperactivation of B cells observed in patients carrying HIV-1 infection, and showed that it can be partly induced by ligation of soluble cleaved CD27 to CD70 on the surface of memory B cells. In paper II, we aimed at comparing the establishment of serum antibody titers and memory B cells after vaccination against measles and rubella in healthy children. We found that the memory B cell pool remained stable also early after vaccination, whereas the corresponding serum IgG titers decayed with time. In contrast, both the serum IgG levels and frequency of blood memory B cells in healthy young adults appeared stable. This implied that the antibody production and memory B cell compartment are two separate entities with independent regulation, and that it takes longer time to establish a stable pool of circulating antibodies. How these two parts of B cell memory are affected by immunosuppressive disease and treatment was addressed in papers III and IV. In paper III, we used a rhesus macaque model for high-dose Doxorubicin treatment, and concluded that the established vaccine-induced memory B cell pool was depleted, contrary to long-lived plasma cells and the resulting serum IgG titers. These observations supported the finding of independent regulation of the two B cell memory compartments, and revealed different sensitivity to chemotherapy. The bone marrow plasma cell niche was additionally studied in an in vitro model for plasma cell – stromal cell cross talk, where we discovered that in vivo relevant concentrations of Doxorubicin could hamper the output of pivotal survival factors from stromal cells. In paper IV, we examined memory B cells and circulating IgG titers in children with rheumatic disease, treated with low-dose Methotrexate and TNF-α inhibition. We noted that serum IgG titers against tetanus were lower in rheumatic patients than in healthy controls, and that patients who had only received one measles vaccine dose had lower levels of measles-specific memory B cells. This stresses the importance for children with rheumatic disease and treatment to follow the full vaccine schedule.
To summarize, this thesis has contributed to enhanced knowledge on how B cell memory is induced, preserved and at risk of disruption by common immune disorders and treatment. Hopefully, our findings can aid future improvement of functional vaccine regimes for immunocompromised children.
List of papers:
I. Dang LV, Nilsson A, Ingelman-Sundberg H, Cagigi A, Gelinck LB, Titanji K, De Milito A, Grutzmeier S, Hedlund J, Kroon FP, Chiodi F. Soluble CD27 induces IgG production through activation of antigen-primed B cells. J Intern Med. 2011 Sep 14.
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II. Kakoulidou M, Ingelman-Sundberg H, Johansson E, Cagigi A, Farouk SE, Nilsson A, Johansen K. Kinetics of antibody and memory B cell responses after MMR immunization in children and young adults. Vaccine. 2012 Nov 19.
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III. Ingelman-Sundberg HM, Saghafian-Hedengren S, Jahnmatz M, Eksborg S, Jonker M, Nilsson A. Selective loss of vaccine-specific memory B cells in a Rhesus Macaque model of chemotherapy: influence of Doxorubicin on immunological memory. Haematologica. 2014 Dec 31.
Fulltext (DOI)
Pubmed
IV. Ingelman-Sundberg HM, Laestadius Å, Chrapkowska C, Mördrup K, Magnusson B, Sundberg E, Nilsson A. Effects of Methotrexate and TNF-alfa inhibition on long-term vaccine immunity against measles, rubella and tetanus in children with rheumatic diseases. [Manuscript]
I. Dang LV, Nilsson A, Ingelman-Sundberg H, Cagigi A, Gelinck LB, Titanji K, De Milito A, Grutzmeier S, Hedlund J, Kroon FP, Chiodi F. Soluble CD27 induces IgG production through activation of antigen-primed B cells. J Intern Med. 2011 Sep 14.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Kakoulidou M, Ingelman-Sundberg H, Johansson E, Cagigi A, Farouk SE, Nilsson A, Johansen K. Kinetics of antibody and memory B cell responses after MMR immunization in children and young adults. Vaccine. 2012 Nov 19.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Ingelman-Sundberg HM, Saghafian-Hedengren S, Jahnmatz M, Eksborg S, Jonker M, Nilsson A. Selective loss of vaccine-specific memory B cells in a Rhesus Macaque model of chemotherapy: influence of Doxorubicin on immunological memory. Haematologica. 2014 Dec 31.
Fulltext (DOI)
Pubmed
IV. Ingelman-Sundberg HM, Laestadius Å, Chrapkowska C, Mördrup K, Magnusson B, Sundberg E, Nilsson A. Effects of Methotrexate and TNF-alfa inhibition on long-term vaccine immunity against measles, rubella and tetanus in children with rheumatic diseases. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Nilsson, Anna
Issue date: 2015-01-22
Rights:
Publication year: 2015
ISBN: 978-91-7549-807-2
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