Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

More documents

Recommendations

Info

Medical Microbiology Section Zusammenfassung T-Zellen spielen eine entscheidende Rolle bei der Bekämpfung der Malaria und sind sowohl an der Kontrolle der Leberstadien, als auch an der Kontrolle der Blutstadien beteiligt. Eine Aktivierung von T-Zellen während der Leberphase induziert keine Pathologie, wodurch diese Phase in der Regel ohne Symptome verläuft. Im Gegensatz dazu wird die Blutphase von der charakteristischen Symptomatik der Malaria und der damit verbundenen Pathologie begleitet. Eine Schlüsselstellung bei der Pathogenese nehmen dabei T-Zellen ein. Insbesondere Th1-Zellen und die damit assoziierten Zytokine IFN-γ und TNF-α scheinen ursächlich an der Pathologie der schweren Malaria beteiligt zu sein. Aus früheren Arbeiten wissen wir, dass CTLA-4 (CD152) an der Kontrolle der T-Zellen beteiligt ist. Dieses Molekül ist ein negativer Regulator auf der Oberfläche von aktivierten T-Zellen und wird im Verlauf der Malaria induziert. Eine Blockade dieses Moleküls in einem Mausmodell der Malaria führt zwar zu einer verstärkten Aktivierung von T-Zellen, aber induziert gleichzeitig eine Pathologie in verschiedenen Organen. Unsere Untersuchungen haben gezeigt, dass die Expression von CTLA-4 zu einer Kontrolle von T-Zellen in verschiedene Geweben führen kann und dadurch das Ausmaß der Entzündung kontrolliert wird. CTLA-4 dependent regulation of T cells during Malaria 52 Summary T cells were shown to play an important role in the control of malaria during the liver stage as well as during the blood stage of the disease. An activation of T cells during the liver phase is not associated with any symptoms, whereas an activation of T cells during the blood stage contribute to the typical symptoms of malaria. T cells were shown to play a key role in the development of pathology. Especially Th1 cells and their characteristic cytokines IFN-γ and TNF-α were shown to be involved in pathology. Recently it was shown that CTLA- 4 (CD152) could regulate the function of T cells. This molecule expressed on the surface of activated T cells and its expression is induced during malaria. A blockade of this molecule leads to an increased activation of T cells but was also accompanied by a severe pathology in various organs. Our studies have shown that an expression of CTLA-4 leads to a control of T cells in peripheral tissues and thus providing a mechanism by which inflammation could be controlled. Introduction T cells play a key role in the control of various pathogens by either providing direct effector molecules or by regulating other branches of the immune system. However the immune response has to be tightly regulated to prevent pathology. Recently, co-stimulatory molecules that deliver negative signals to T cells were described. CTLA-4 (CD152) has a sequence homology to CD 28 but is only expressed on activated T cells. Several studies have shown that CTLA-4 plays an essential inhibitory role and is involved in the induction of peripheral tolerance. Studies at the Bernhard Nocht Institute have shown that during human malaria CTLA-4 is Figure 1: Serum levels of liver-enzymes in P. berghei infected mice at day 8 after infection. (A) P. berghei infected displayed an increased level of liver-enzymes that further increased dramatically upon blockade of CTLA-4 by a monoclonal antibody against CTLA-4. (B) P. berghei infected mice that are deficient for pro-inflammatory cytokines are resistant for liver-pathology induced by CTLA-4 blockade.
expressed at a very high number on T cells. Since in human as well as in rodent malaria T cells are involved in protection, but at the same time in pathology, the T cell response has to be tightly regulated. We investigated in the current study how CTLA-4 is involved in this regulation. Project Rescription and Results During the course of malaria several organs develop pathology. In the present work we studied the mechanisms leading to inflammation of different tissue during the erythrocyte stage of rodent malaria. During infection mice developed an inflammation of the liver, associated with infiltration of T cells, although only little tissue damage could be observed. Histological analysis revealed the presence of CTLA-4 positive T cells in the liver parenchyma. To study the influence of CTLA-4 expression on liver inflammation, mice were treated with an antibody against CTLA-4. Treated mice suffered from a dramatically increased liver pathology. Using cytokine-deficient mice we found that pathology was dependent on the presence of IL-12 and IFN-γ. To further study the mechanisms that lead to an enhanced pathology, we analyzed cytokine-production from liver derived T cells. In infected mice the frequency of IFN-g producing cells in the liver was low. In contrast, in anti- CTLA-4 treated mice larger numbers of IFN-γ producing cells were detectable. Our results indicate that activated T cells during the erythrocyte stage of malaria can induce pathology due to secretion of pro-inflammatory cytokines. Moreover, these results provide evidence that CTLA-4 expression can restrict T cell function in inflamed organs and might therefore prevent pathology. 53 Selected Publications • Jacobs T., Graefe, S.E.B., Niknafs, S., Gaworski, I. & Fleischer, B. (2002). Murine malaria is exacerbated by CTLA-4 blockade. J. Immunol. 169: 2323-2329 • Jacobs T., Plate T., Gaworski G. & Fleischer B. (2004). CTLA-4 ligation prevents T-cell induced liver injury during P. bergei blood-stage malaria. Eur. J. Immunol. 34: 972-80. Funding • Studienstiftung des Deutschen Volks Investigators • Thomas Jacobs • Iris Gaworski • Sebastian Graefe • Thorsten Lieke • Tanja Plate • Susanne Tartz Medical Microbiology Section
Page 1 and 2: BERNHARD NOCHT INSTITUTE FOR TROPIC
Page 3 and 4: Human genetic variants influencing
Page 5 and 6: Research Funding / Haushaltsmittel
Page 7 and 8: Introduction The appearance of SARS
Page 9 and 10: tive project with the Faculty of Me
Page 11 and 12: since this group headed by Dr. Chri
Page 13 and 14: Vorwort Das Erscheinen der schweren
Page 15 and 16: AIDS-Forschung hat eine lange zurü
Page 17 and 18: europäisches Konsortium mit 8 Part
Page 19 and 20: Parasitology Section Selected Scien
Page 21 and 22: Zusammenfassung des Sprechers Die S
Page 23 and 24: Research Group Clos (Leishmaniasis
Page 25 and 26: Figure 2: Incidence of ALA in Hué
Page 27 and 28: jects were assigned to receive dilo
Page 29 and 30: is increased in the first 24 h of h
Page 31 and 32: the populations from the endemic ar
Page 33 and 34: CQR Dd2. In order to determine whet
Page 35 and 36: Project Description and Results A g
Page 37 and 38: Project Description and Results Ado
Page 39 and 40: 39 Parasitology Section Figure 2: S
Page 41 and 42: The paraflagellar rod, a crosshatch
Page 43: Figure 1: Suggested in vivo develop
Page 46 and 47: Medical Microbiology Section Chairm
Page 48 and 49: Medical Microbiology Section Zusamm
Page 50 and 51: Medical Microbiology Section Medica
Page 54 and 55: Medical Microbiology Section Murine
Page 56 and 57: Medical Microbiology Section The ro
Page 58 and 59: Medical Microbiology Section Zusamm
Page 60 and 61: Medical Microbiology Section Immunp
Page 62 and 63: Medical Microbiology Section Role o
Page 64 and 65: Medical Microbiology Section Elimin
Page 66 and 67: Medical Microbiology Section Charac
Page 68 and 69: Medical Microbiology Section Identi
Page 70 and 71: Medical Microbiology Section A dry-
Page 73 and 74: Tropical Medicine Section Selected
Page 75 and 76: Zusammenfassung des Sektionsspreche
Page 77 and 78: Kumasi Centre for Collaborative Res
Page 79 and 80: Data of twin studies and evidence f
Page 81 and 82: Figure 1: Changing patterns of mala
Page 83 and 84: Zusammenfassung In einer Studie an
Page 85 and 86: low level chronic replication of th
Page 87 and 88: The KCCR Team and the main laborato
Page 89 and 90: Kooperierende Institutionen • Kwa
Page 91: Figure 2: Study sites in and around
Page 94 and 95: Clinical Department Department Head
Page 96 and 97: Clinical Department Bericht des Abt
Page 98 and 99: Clinical Department Staff Clinical
Page 100 and 101: Clinical Department Cardiac impairm
Page 102 and 103:
Clinical Department Persistence and
Page 104 and 105:
106
Page 106 and 107:
Administration and Public Relations
Page 108 and 109:
Administration and Public Relations
Page 110 and 111:
112
Page 112 and 113:
Education and Teaching Diploma Thes
Page 114 and 115:
Education and Teaching Parasitology
Page 116 and 117:
Education and Teaching Lars Volkman
Page 118 and 119:
Education and Teaching The objectiv
Page 120 and 121:
Education and Teaching Ziel des Kur
Page 122 and 123:
Education and Teaching Institute Fa
Page 124 and 125:
Education and Teaching Lectures and
Page 126 and 127:
Education and Teaching Training for
Page 128 and 129:
Seminar Programme 2002 Prof. Aileen
Page 130 and 131:
Seminar Programme Dr. Stefan Martin
Page 132 and 133:
Symposia and Meetings 2002 Symposia
Page 134 and 135:
Symposia and Meetings 2003 May 13 t
Page 136 and 137:
138
Page 138 and 139:
Staff Activities Staff Activities A
Page 140 and 141:
Staff Activities PD Dr. Joachim Clo
Page 142 and 143:
Staff Activities Editorial Activiti
Page 144 and 145:
Staff Activities Prof. Dr. Rolf Hor
Page 146 and 147:
Staff Activities Prof. Dr. Christia
Page 148 and 149:
Staff Activities Prof. Dr. Egbert T
Page 150 and 151:
152
Page 152 and 153:
Publications Book chapters and Mono
Page 154 and 155:
Publications Herbst R, Ott C, Jacob
Page 156 and 157:
Publications Supali T, Wibowo H, Ru
Page 158 and 159:
Publications Scholze H and Tannich
Page 160 and 161:
Publications Graefe SE, Meyer BS, M
Page 162 and 163:
Publications Schulz A, Mellenthin K
Page 164 and 165:
166
Page 166 and 167:
Appendix 01. Januar 2002 Das BNI wi
Page 168 and 169:
Appendix 01. Oktober 2002 Gemeinsam
Page 170 and 171:
Appendix 01. April 2003 Ergebnis de
Page 172 and 173:
Appendix 01. Juni 2003 Fernsehrepor
Page 174 and 175:
Appendix November 2003 Inauguration
Page 176 and 177:
Appendix red by solar energy could
Page 178 and 179:
Appendix Ansprache von Dr. Thomas F
Page 180 and 181:
Diary 2004/2005 12.-14. November 20
show all

Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Create successful ePaper yourself

Delete template?

Save as template?