Skip to main content
Top
Published in: Molecular and Cellular Pediatrics 1/2018

Open Access 01-12-2018 | Research

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis

Authors: Teresa Schleker, Eva-Maria Jacobsen, Benjamin Mayer, Gudrun Strauss, Klaus-Michael Debatin, Carsten Posovszky

Published in: Molecular and Cellular Pediatrics | Issue 1/2018

Login to get access

Abstract

Background

Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.

Methods

We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H3-thymidine detected in a beta counter.
The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.

Results

Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells.
Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.

Conclusions

Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that—provided a normal distribution and count of lymphocyte subgroups—patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.
Appendix
Available only for authorised users
Literature
1.
go back to reference Rufo PA, Bousvaros A (2006) Current therapy of inflammatory bowel disease in children. Paediatr Drugs 8(5):279–302CrossRefPubMed Rufo PA, Bousvaros A (2006) Current therapy of inflammatory bowel disease in children. Paediatr Drugs 8(5):279–302CrossRefPubMed
2.
go back to reference Della Corte C, Sartorelli MR, Sindoni CD, Girolami E, Giovannelli L, Comparcola D et al (2012 Jul) Autoimmune hepatitis in children: an overview of the disease focusing on current therapies. Eur J Gastroenterol Hepatol 24(7):739–746CrossRefPubMed Della Corte C, Sartorelli MR, Sindoni CD, Girolami E, Giovannelli L, Comparcola D et al (2012 Jul) Autoimmune hepatitis in children: an overview of the disease focusing on current therapies. Eur J Gastroenterol Hepatol 24(7):739–746CrossRefPubMed
3.
go back to reference Schleker T, Speth F, Posovszky C (2015/2016) Impfen beim immunsupprimierten Kind. pädiatrische praxis. 85:363–384 Schleker T, Speth F, Posovszky C (2015/2016) Impfen beim immunsupprimierten Kind. pädiatrische praxis. 85:363–384
4.
go back to reference Robert Koch Institut (2012) Impfquoten bei der Schuleingangsuntersuchung in Deutschland 2010. Epidemiologisches Bulletin 16:135-139 Robert Koch Institut (2012) Impfquoten bei der Schuleingangsuntersuchung in Deutschland 2010. Epidemiologisches Bulletin 16:135-139
5.
go back to reference Cullen G, Baden RP, Cheifetz AS (2012 Dec) Varicella zoster virus infection in inflammatory bowel disease. Inflamm Bowel Dis 18(12):2392–2403CrossRefPubMed Cullen G, Baden RP, Cheifetz AS (2012 Dec) Varicella zoster virus infection in inflammatory bowel disease. Inflamm Bowel Dis 18(12):2392–2403CrossRefPubMed
6.
go back to reference Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y et al (2014) Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohn’s Colitis 8(6):443–468CrossRef Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y et al (2014) Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohn’s Colitis 8(6):443–468CrossRef
7.
go back to reference Siegrist C (2008) Vaccine immunology. Vaccine 5:17–36 Siegrist C (2008) Vaccine immunology. Vaccine 5:17–36
8.
go back to reference Shetty AK, Winter MA (2012) Immunization of children receiving immunosuppressive therapy for cancer or hematopoietic stem cell transplantation. Ochsner J 12(3):228–243PubMedPubMedCentral Shetty AK, Winter MA (2012) Immunization of children receiving immunosuppressive therapy for cancer or hematopoietic stem cell transplantation. Ochsner J 12(3):228–243PubMedPubMedCentral
9.
go back to reference Heijstek MW, Ott de Bruin LM, Bijl M, Borrow R, van der Klis F, Kone-Paut I et al (2011 Oct) EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis 70(10):1704–1712CrossRefPubMed Heijstek MW, Ott de Bruin LM, Bijl M, Borrow R, van der Klis F, Kone-Paut I et al (2011 Oct) EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis 70(10):1704–1712CrossRefPubMed
10.
go back to reference Nafe LA, Dodam JR, Reinero CR (2014 Jul) In-vitro immunosuppression of canine T-lymphocyte-specific proliferation with dexamethasone, cyclosporine, and the active metabolites of azathioprine and leflunomide in a flow-cytometric assay. Can J Vet Res 78(3):168–175PubMedPubMedCentral Nafe LA, Dodam JR, Reinero CR (2014 Jul) In-vitro immunosuppression of canine T-lymphocyte-specific proliferation with dexamethasone, cyclosporine, and the active metabolites of azathioprine and leflunomide in a flow-cytometric assay. Can J Vet Res 78(3):168–175PubMedPubMedCentral
11.
go back to reference Barten MJ, Gummert JF, van Gelder T, Shorthouse R, Morris RE (2001) Flow cytometric quantitation of calcium-dependent and -independent mitogen-stimulation of T cell functions in whole blood: inhibition by immunosuppressive drugs in vitro. J Immunol Methods 253(1):95–112CrossRefPubMed Barten MJ, Gummert JF, van Gelder T, Shorthouse R, Morris RE (2001) Flow cytometric quantitation of calcium-dependent and -independent mitogen-stimulation of T cell functions in whole blood: inhibition by immunosuppressive drugs in vitro. J Immunol Methods 253(1):95–112CrossRefPubMed
12.
go back to reference Dahlén R, Strid H, Lundgren A, Isaksson S, Raghavan S, Magnusson MK et al (2013) Infliximab inhibits activation and effector functions of peripheral blood T cells in vitro from patients with clinically active ulcerative colitis. Scand J Immunol 78(3):275–284CrossRefPubMed Dahlén R, Strid H, Lundgren A, Isaksson S, Raghavan S, Magnusson MK et al (2013) Infliximab inhibits activation and effector functions of peripheral blood T cells in vitro from patients with clinically active ulcerative colitis. Scand J Immunol 78(3):275–284CrossRefPubMed
13.
go back to reference Salinas GF, De Rycke L, Barendregt B, Paramarta JE, Hreggvidstdottir H, Cantaert T et al (2013 Jun) Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. Ann Rheum Dis 72(6):1037–1043CrossRefPubMed Salinas GF, De Rycke L, Barendregt B, Paramarta JE, Hreggvidstdottir H, Cantaert T et al (2013 Jun) Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. Ann Rheum Dis 72(6):1037–1043CrossRefPubMed
14.
go back to reference Stone KD, Feldman HA, Huisman C, Howlett C, Jabara HH, Bonilla FA (2009) Analysis of in vitro lymphocyte proliferation as a screening tool for cellular immunodeficiency. Clin Immunol 131(1):41–49CrossRefPubMed Stone KD, Feldman HA, Huisman C, Howlett C, Jabara HH, Bonilla FA (2009) Analysis of in vitro lymphocyte proliferation as a screening tool for cellular immunodeficiency. Clin Immunol 131(1):41–49CrossRefPubMed
15.
go back to reference Pacocha SE, Oriente A, Huang S, Essayan DM (1999) Regulation of antigen-induced human T-lymphocyte responses by calcineurin antagonists. J Allergy Clin Immunol 104(4):828–835CrossRefPubMed Pacocha SE, Oriente A, Huang S, Essayan DM (1999) Regulation of antigen-induced human T-lymphocyte responses by calcineurin antagonists. J Allergy Clin Immunol 104(4):828–835CrossRefPubMed
16.
go back to reference Teunissen MB, Pistoor FH, Rongen HA, Kapsenberg ML, Bos JDA (1992 Apr) Comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro. Transplantation 53(4):875–881CrossRefPubMed Teunissen MB, Pistoor FH, Rongen HA, Kapsenberg ML, Bos JDA (1992 Apr) Comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro. Transplantation 53(4):875–881CrossRefPubMed
17.
go back to reference Gummert JF, Barten MJ, Sherwood SW, van Gelder T, Morris RE (1999 American Society for Pharmacology and Experimental Therapeutics) Pharmacodynamics of Immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics. J Pharmacol Exp Ther 291(3):1100–1112PubMed Gummert JF, Barten MJ, Sherwood SW, van Gelder T, Morris RE (1999 American Society for Pharmacology and Experimental Therapeutics) Pharmacodynamics of Immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics. J Pharmacol Exp Ther 291(3):1100–1112PubMed
18.
go back to reference Cook JO, Lai W, McGrane B (1983) The effect of suboptimal concentrations of mitogens on the immunosuppressive action of azathioprine and prednisolone on human lymphocytes in vitro. J Immunopharmacol 5(4):257–275CrossRefPubMed Cook JO, Lai W, McGrane B (1983) The effect of suboptimal concentrations of mitogens on the immunosuppressive action of azathioprine and prednisolone on human lymphocytes in vitro. J Immunopharmacol 5(4):257–275CrossRefPubMed
19.
go back to reference Dupont E, Schandene L, Denys C, Wybran J (1986) Differential in vitro actions of cyclosporin, methylprednisolone, and 6-mercaptopurine: implications for drugs’ influence on lymphocyte activation mechanisms. Clin Immunol Immunopathol 40(3):422–428CrossRefPubMed Dupont E, Schandene L, Denys C, Wybran J (1986) Differential in vitro actions of cyclosporin, methylprednisolone, and 6-mercaptopurine: implications for drugs’ influence on lymphocyte activation mechanisms. Clin Immunol Immunopathol 40(3):422–428CrossRefPubMed
20.
go back to reference Kyles AE, Gregory CR, Craigmill AL (2000 Aug) Comparison of the in vitro antiproliferative effects of five immunosuppressive drugs on lymphocytes in whole blood from cats. Am J Vet Res 61(8):906–909CrossRefPubMed Kyles AE, Gregory CR, Craigmill AL (2000 Aug) Comparison of the in vitro antiproliferative effects of five immunosuppressive drugs on lymphocytes in whole blood from cats. Am J Vet Res 61(8):906–909CrossRefPubMed
21.
go back to reference Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Bühler S (2017) Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation—a systematic review of randomized trials, observational studies and case reports. Vaccine 35(9):1216–1226CrossRefPubMed Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Bühler S (2017) Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation—a systematic review of randomized trials, observational studies and case reports. Vaccine 35(9):1216–1226CrossRefPubMed
Metadata
Title
Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis
Authors
Teresa Schleker
Eva-Maria Jacobsen
Benjamin Mayer
Gudrun Strauss
Klaus-Michael Debatin
Carsten Posovszky
Publication date
01-12-2018
Publisher
Springer Berlin Heidelberg
Published in
Molecular and Cellular Pediatrics / Issue 1/2018
Electronic ISSN: 2194-7791
DOI
https://doi.org/10.1186/s40348-018-0079-0

Other articles of this Issue 1/2018

Molecular and Cellular Pediatrics 1/2018 Go to the issue