Course Outline

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Course outline for MEDSCI 708
ADVANCED IMMUNOLOGY AND IMMUNOTHERAPY 2011
Course co-ordinators
Professor John Fraser, A/Professor Geoffrey Krissansen
jd.fraser@auckland.ac.nz
gw.krissansen@auckland.ac.nz
1. Academic teaching:
Professor John Fraser, Assoc. Prof. Geoffrey Krissansen, Assoc. Prof. Thomas Proft and Dr
Kevin Sun.
This paper is intended to give students insight into current topics of immunology at an
advanced level. Prior knowledge of basic immunology is therefore important. The
course will most likely attract those students who have completed the 3 rd year
Immunology paper and wish to advance in this field or to extend their knowledge
beyond the general coverage of 3 rd year.
2. Assessment
60% - exam 30% - assignments/essays 10% - oral presentation
3. Course outline
This paper will provide an introduction to advanced topics in Immunology over 12
tutorial sessions. There will be 6 x 2.0 hr lectures which will address specific areas
such as the genes and proteins involved in immune recognition for both the adaptive
and immune response, cell adhesion molecules and their role in regulating cell-cell
contact, migration and homing, intracellular signalling mechanisms that determine
immune outcomes, the mechanisms by which the immune system learns “self” from
“non-self”, cytokines and chemokines, mechanisms of inflammation and disease, the
interaction between tumours and the immune response, and current immunotherapies
will all be presented. There will be 6 x 2.0 hr tutorials, where each tutorial follows a
lecture on one of the six topics. Thus, every second week, students will be required to
participate in the tutorial by presenting a seminar on a discussion paper from the
previous weeks lecture to the class.
The lecture
As above, there will be 12 sessions (lecture followed by a tutorial) of 2.0 hours each
presented by a different person every two weeks. Students are required to read the
reviews prior to the lecture. Each session is dedicated to one aspect of current
immunology research. Most of our attention will be focused on areas that have
developed significantly in the past decade. We cannot hope to cover all aspects of
this very broad area or research so we have selected topics that we think are most
important to our current understanding and for which there have been recent
significant developments.
4. Student seminar/tutorial
Every second week, a subgroup of students will be required to present a discussion
paper to the class. The tutor will assess the student’s presentation with a mark out of
10. It is normal practice to present an in depth appraisal of a paper giving an

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overview of the area that it addresses, the question it tackles, any hypotheses that
are tested, the methods used, the results achieved and of course the interpretation of
the data and conclusions about how this paper has advanced to field. Please note: It
is essential to present the actual figures of the article (main figures at least) so
that your audience can judge the credibility of the results. The preferred medium
is powerpoint files which will be displayed using our datashow projector (see
description of Discussion papers below). Most students choose to use a PowerPoint
presentation, but you must let the tutor know ahead of time, and provide the files
before the day of presentation.
5. Essay
A 3000-word essay on one of the six course topics. You may wish to discuss the
scope of your essay with the lecturer before you begin writing. Essays are to be
submitted to the Departmental Secretary by 5:00pm Friday 10 th June 2011.
Extensions must be requested in writing to the course coordinators. This is almost
two weeks after the final tutorial session and should give you sufficient time to
concentrate on your exam.
6. Assignment of papers and essays
At the beginning of the course, we will arbitrarily assign you to one or more discussion
papers. The number you are assigned will depend on how many students we have in
the course each year but will likely be one, and no more than two. You may
“negotiate” with other students if you wish to change your time or topic but must let
the course coordinators know of any changes.
Several essay topics will be provided and you can choose a 1,2,3 priority. This will be
done in the first session. This is in order to distribute students evenly across the
essay topics
7. Advice
The following facilities are available to you in the Division:
Tearooms-
level 3 Clinical Building
Photocopiers- level 3 Pathology Building 504
level 3 Clinical Building
Please note that the secretaries in the Department may be able to assist with photocopying,
but that this is not a service which can be provided instantaneously. Please provide material
well in advance.
All teaching in MEDSCI 708 will be in Room 502-034.
PDF copies of all articles selected for discussion will be placed on a website for you to read or
print-off.
Important
The essay must be an original work of scholarship. Unacknowledged copying or plagiarism in
completing this work is treated as an examination offence (see University Calendar).
Word limit for the essay = 3,000 words.
Any photocopying of presentation handouts must be done before the day of the presentation.
The secretaries may not be able to photocopy materials on the day of the presentation.

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8. Review papers
All students prior to the tutorial must read the review papers. Make notes about what
you think are important points or questions you have to bring to the tutorial.
9. Discussion papers – Presentations
Discussion papers will be assigned to individual students who will be asked to present
a 15 or 20 minute (depending on class numbers) oral synopsis of a discussion paper
pointing out the significant aspects of the research and how the conclusions were
reached. The presentation will be followed by 5 minutes of questions from the lecturer
and class colleagues. Please note: It is essential to present the actual figures of
the article (main figures at least) so that your audience can judge the credibility
of the results. Assignments of names to discussion papers will be done at the
beginning of the topic. All students should read the discussion papers and offer
enlightened comments during the tutorial sessions. The tutor’s role is to ask
questions pertinent to the subject and to fill in any gaps. A maximum of 10
powerpoint slides will be allowed. Presentations must not be allowed to go over
the allocated time (marks will be deducted).
10. Final exam
All material presented in the course is examinable.

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Lecture summaries
Wednesday 8:00am – 10.00pm. Room 502-034.
March 2nd and 9 th Topic 1- Antigen recognition in adaptive and
innate immunity – John Fraser
The immune response of higher organisms has two distinct but interlinked systems – the
innate and adaptive response. The adaptive response uses a set of rearranging genes to
create antibody and T cell Receptor molecules with a vast repertoire of antigen recognition
surfaces. The innate response relies on a wide array of fixed pattern recognition receptors
that bind to molecules only found on microbes. This session looks at both systems from the
standpoint of antigen recognition; the types of molecules that are involved such as MHC and
T cell Receptor and TLR and other innate receptors such as the intracellular inflammasome
and their roles, and the way in which different types of antigens are recognised and cells are
triggered. The session will also address one of the most compelling questions in
immunology, how do these molecules distinguish small differences between self and non-self
antigens from such small amounts of antigen? We hope by the end of this session, you will
have an appreciation for the exquisite complexity and diversity of antigen recognition in both
the adaptive and innate responses and how both work together to provide the means to
discriminate and respond to pathogens.
March 16 st and March 23 rd Topic 2- Cell adhesion: Roles in
lymphocyte recirculation, trafficking, and microenvironmentspecific
homing - Geoffrey Krissansen
Cell to cell, and cell to matrix interactions are fundamental biological processes which
regulate cell motility, migration, localisation, differentiation, and proliferation in all multicellular
organisms. In this topic we will define the families of cell adhesion molecules that sit on the
outside of immune cells enabling cells to move within tissues like primitive amoeba, to
communicate with one another, and to respond to their immediate microenvironment. The
structures, functions, and expression of various cell adhesion molecules involved in the latter
processes, including the Integrins, Ig CAMs, Cadherins, Selectins, Mucins, and extracellular
matrix molecules will be briefly addressed. The fascinating, “highly controlled” multistep
process by which leukocytes extravasate from blood vessels will be explored. The "area
code" molecules, in particular the chemokines, that direct leukocyte traffic, and
microenvironment-specific lymphocyte homing will be analysed. By the end of the session you
will understand how the efficiency of the immune system is increased by the
immunolocalization of specialized leukocytes to sites in the body where they are most likely to
find antigen, and/or enhance the immune response.
March 30 th and 6 th April Topic 3- NK Receptors – John Fraser
There are two very distinct pathways by which foreign peptides are generated and presented
on the surface of cells in the context of MHC. The endogenous and exogenous pathways of
antigen presentation will be discussed. Recent evidence has revealed that a number of
pathogens selectively target elements of these pathways to prevent the immune system from
recognising them reflecting the never ending battle between host and pathogen. Papers
concerning these recent discoveries will be highlighted.
April 27 th and May 4 th Topic 4- Antigen Presentation – Thomas
Proft
There are two very distinct pathways by which foreign peptides are generated and presented
on the surface of cells in the context of MHC. The endogenous and exogenous pathways of
antigen presentation will be discussed. Recent evidence has revealed that a number of
pathogens selectively target elements of these pathways to prevent the immune system from

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recognising them reflecting the never ending battle between host and pathogen. Papers
concerning these recent discoveries will be highlighted.
May 11 th and 18 th Topic 5- Advances in understanding
inflammatory disease – Geoffrey Krissansen
Inflammation is normally a benign short-lived reaction mediated by vascular and immune
systems, which is designed primarily to defend the body against invaders. Uncontrolled or
chronic inflammation as seen in autoimmunity is abnormal and underlies the pathogenesis of
many immune diseases. Therefore, understanding the mechanisms of inflammation and
devising ways to prevent it are high priorities for biomedical research. In this topic we will
explore how specific leukocyte types, cell adhesion molecules, chemokines, and cytokines
contribute to the progression and severity of inflammatory-based diseases when the immune
response goes awry. We will examine the roles of T regulatory cells (Tregs), fondly called the
guardians of our immune system, and their unique relationship with certain integrins. We will
touch on potential strategies to treat inflammatory disease.
May 25 th and 1 st June Topic 6- Tumour Immunology – Kevin Sun
Numerous immune effector cells and molecules participate in the recognition and destruction
of cancer cells. But cancer cells can avoid such immunosurveillance. The interaction between
the immune system and cancer cells determines the fortune of tumours. A plethora of
different approaches to cancer immunotherapy are being now being trialed to combat solid
tumours, with varying degrees of success. Cancer immunotherapy is providing unique
insights into tumor immunology, and the properties of tumours that must be overcome if the
human immune system is to be harnessed as a weapon to fight cancer. In this topic you will
study some of the approaches being used, and will learn how tumours interact with, and avoid
the immune response.

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Reference articles
Papers in pdf format are available for download at http://cmb1.auckland.ac.nz/medsci708
1. Recognition by the adaptive and innate immune system -
John Fraser
REVIEWS
Germain RN 2004. An innately interesting decade of research in immunology Nature Medicine 10:
1307-1320. This is a rich summary of the past 10 years’ discovery of the mechanisms for innate
immune recognition written by a respected immunologist. It provides all the references to the key
papers on several very active subjects.
Cooper, M and Alder M (2006) The evolution of the innate and adaptive immune systems Cell 124
815-822. This review covers the extraordinary process of evolution of antigen recognition from
simply innate receptors to complex TcR and Ig molecules that rearrange.
Shizuo Akira, Satoshi Uematsu and Osamu Takeuchi (2006) Pathogen Recognition and Innate
Immunity Cell 124 783-80. An excellent overview of innate pattern recognition
Fabio Martinon, Annick Mayor, Jürg Tschopp (2009) The Inflammasomes: Guardians of the Body
Annual Review of Immunology, Vol. 27: 229-265 This is a recent review on the inflammasome an
innate recognition system that responds to intracellular changes. It has been linked to chronic
inflammatory diseases such as gout and type II diabetes.
DISCUSSION PAPERS
Stephanie C. Eisenbarth, Oscar R. Colegio, William O’Connor Jr, Fayyaz S. Sutterwala & Richard A.
Flavell (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of
aluminium adjuvants Nature 453 1122-1126 This paper reveals the long sought after mechanism of
the widely used adjuvant Alum; a compound used in most vaccines to enhance the B cell immune
response to antigen.
Oliver Schulz, Sandra S. Diebold, Margaret Chen, Tanja I. Naslund , Martijn A. Nolte1, Lena
Alexopoulou, Yasu-Taka Azuma, Richard A. Flavell, Peter Liljestrom & Caetano Reis e Sousa (2005)
Toll-like receptor 3 promotes cross-priming to virus-infected cells Nature 433: 887-891. This paper is
a good example of how the adaptive and innate recognition work together to define the type of
response to a viral infection and how important innate immunity is to an effective CD4/CD8 response
to virus.
Darrell J. Irvine, Marco A. Purbhoo, Michelle Krogsgaard, Mark M. Davis (2002) Direct observation
of ligand recognition by T cells Nature 419 845-849 This paper was a landmark which used new
imaging technology and fluorescent probes to actually measure how many peptides it takes to
stimulate a T cells. The results were remarkable.
2. Cell Adhesion and leukocyte trafficking - Geoff Krissansen
REVIEW
Salmi M, Jalkanen S (2005). Cell-surface enzymes in control of leukocyte trafficking. Nat Rev
Immunol. 5:760-71.
Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte
adhesion cascade updated. Nat Rev Immunol. 7: 678-89, 2007.

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Sigmundsdottir H, Butcher EC. Environmental cues, dendritic cells and the programming of tissueselective
lymphocyte trafficking. Nat Immunol. 9: 981-7, 2008.
DISCUSSION PAPERS
McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA,
Kubes P. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330:
362-6, 2010.
Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. (2007) DCs
metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine
CCL27. Nat Immunol. 8: 285-293.
Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H,
Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH. (2006) Generation of gut-homing
IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157-1160.
Veerman KM, Williams MJ, Uchimura K, Singer MS, Merzaban JS, Naus S, Carlow DA, Owen P,
Rivera-Nieves J, Rosen SD, Ziltener HJ. (2007) Interaction of the selectin ligand PSGL-1 with
chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs.
Nat Immunol. 8: 532-539.
Uchimura K, Gauguet JM, Singer MS, Tsay D, Kannagi R, Muramatsu T, von Andrian UH, Rosen SD
(2005). A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases
expressed in high endothelial venules. Nat Immunol. 6:1105-1113.
3. NK recognition receptors – “missing self” – John Fraser
REVIEWS
Lanier, L.L. Natural killer cell receptor signaling. Curr Opin Immunol 15, 308-14 (2003).
Krzewski K and Strominger JL (2008) The killer’s kiss: the many functions of NK cell immunological
synapse Curr. Opin. Cell. Biol. 20:597-605
Lodoen MB, Lanier LL. Viral modulation of NK cell immunity. Nat Rev Microbiol 3, 59-69 (2005).
Trowsdale J, Betz AG. Mother's little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol
7, 241-6 (2006).
DISCUSSION PAPERS
Braud, V.M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391,
795-9 (1998).
Arase, H., Mocarski, E.S., Campbell, A.E., Hill, A.B. & Lanier, L.L. Direct recognition of
cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323-6 (2002).
Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus
costimulatory activity of NKG2D. Nat Immunol 3, 1142-9 (2002).
Culley FJ, Johnson M. et al., 2009 Natural killer cell signal integration balances synapse symmetry
and migration PLoS Biology 2009 7 1-12
4. Antigen processing and presentation – Thomas Proft
REVIEW

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Brodsky FM, Lem L, Solache A, Bennett EM. 1999. Human pathogen subversion of antigen
presentation. Immunol. Rev. 168: 199-215.
Koopmann JO, Hämmerling GJ, Momburg F. 1997. Generation, intracellular transport and loading of
peptides associated with MHC class I molecules. Curr. Opin. Immunol. 9: 80-8.
Mellman I, Steinman RM. 2001. Dendritic cells: specialized and regulated antigen processing
machines. Cell. 106: 255-8.
Brocke P, Garbi N, Momburg F, Hämmerling GJ. 2002. HLA-DM, HLA-DO and tapasin: functional
similarities and differences. Curr. Opin. Immunol. 14: 22-9.
Note: Immunol. Rev. Vol 207 (2005) is dedicated to “Antigen processing and presentation” and
contains more review articles for those who would like to read further.
DISCUSSION PAPERS
Narayan, K. et al. HLA-DM targets the hydrogen bond between the histidine at position 81 and
peptide to dissociate HLA-DR-peptide complexes. Nature Immunol. 8: 92-100 (2007)
Blander, JM & Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by
dendritic cells. Nature 440: 808-812 (2006)
Schmid, D, Pypaert, M., Munz, C. Antigen-loading compartments for major histocompatibility
complex class II molecules continuously receive input from autophagosomes. Immunity 26: 79-92
(2007)
Peaper, DR & Cresswell, P. The redox activity of Erp57 is not essential for its function in MHC class I
peptide loading. Proc. Natl. Acad. Sci. USA 105: 10477-10482 (2008)
Van der Wel, N. et al. Mycobacterium tuberculosis and Mycobacterium leprae translocate from the
phagolysosome to the cytosol in myeloid cells. Cell 129: 1287-1298 (2007).
5. Inflammation & inflammatory disease – Geoffrey Krissansen
REVIEWS
Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature 454: 445-54,
2008.
Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev
Immunol. 6: 508-519, 2006.
Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat
Immunol. 9: 239-44, 2008.
DISCUSSION PAPERS
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating
mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104-7, 2010. NEWS &
VIEWS Calfee CS, Matthay MA. Clinical immunology: Culprits with evolutionary ties. Nature
464:41-2, 2010.
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S.
CTLA-4 control over Foxp3+ regulatory T cell function. Science 322: 271-5, 2008.

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Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X,
Reichardt LF, Bluestone JA, Sheppard D. Loss of integrin alpha(v)beta8 on dendritic cells causes
autoimmunity and colitis in mice. Nature 449: 361-365, 2007.
Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and
regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-60, 2007.
Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, Shen H, Yang
X, Chen YH. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune
homeostasis. Cell 133: 415-26, 2008.
6. Tumour immunology – Kevin Sun
REVIEWS
Zitvogel L, Tesniere A, Kroemer G.(2006) Cancer despite immunosurveillance: immunoselection and
immunosubversion. Nat Rev Immunol 6(10): 715-27.
Bhardwaj N. Harnessing the immune system to treat cancer. (2007) J Clin Invest 117: 1130-1136.
Tacken PJ. de Vries IJ. Torensma R. Figdor CG. (2007) Dendritic-cell immunotherapy: from ex vivo
loading to in vivo targeting. Nat Rev Immunol 7(10):790-802.
Zou W. (2005) Immunosuppressive networks in the tumour environment and their therapeutic
relevance. Nat Rev Cancer. 5:263-74.
DISCUSSION PAPERS
Eisenring M, vom Berg J, Kristiansen G, Saller E, Becher B. (2010) IL-12 initiates tumor rejection
via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol.
11(11):1030-8.
Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, Dhanji S, Nguyen LT,
Gronski MA, Morre M, Assouline B, Lahl K, Sparwasser T, Ohashi PS, Mak TW. (2009) Adjuvant
IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies.
Nat Med. 15(5):528-36
Pastor F, Kolonias D, Giangrande PH, Gilboa E. (2010) Induction of tumour immunity by targeted
inhibition of nonsense-mediated mRNA decay. Nature. 465(7295):227-30.
Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G, Sadelain M. (2007)
T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor
rejection. Nat Med. 13(12):1440-9.
Tanaka H, Kono E, Tran CP, Miyazaki H, Yamashiro J, Shimomura T, Fazli L, Wada R, Huang J,
Vessella RL, An J, Horvath S, Gleave M, Rettig MB, Wainberg ZA, Reiter RE. (2010) Monoclonal
antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance.
Nat Med. 16(12):1414-20.