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Timeline of Immunology

Timeline of Immunology

2

al Sciences al Hashemi Hashemi S.M.

[email protected] [email protected] Department of , of Department

Seyed Mahmoud Hashemi, Ph.D. Hashemi, Mahmoud Seyed

SchoolMedicine, of Shahid BeheshtiMedicof University ﻭﺍﻳﻣﻭﻧﻭﻟﻭژی ﻣﻘﺩﻣﻪ ﺗﺎﺭﻳﺧﭼﻪ ﺍﻳﻣﻭﻧﻭﻟﻭژی 9/30/2016 Basic Immunology: Functions and Disorders Cellular and Molecular of the [With Access Code] Immunology, 8e by Abul K. 9781416055693 Abbas MBBS, Andrew H. H. Basic Immunology: Functions and Disorders Lichtman MD PhD and Shiv of the Immune System [With Access Code] Pillai PhD (Aug 28, 2014) by Abul K. Abbas , Andrew H. Lichtman , David L. Baker )

8e (Immunology (Roitt)) Paperback – October 1, 2012by David Male MA Janeway's Immunobiology PhD (Author), Jonathan Brostoff MA Paperback – July 25, 2011 by DM DSc(Med) FRCP Kenneth Murphy (Author) FRCPath (Author), & 2more

Kuby Immunology (Kindt, Kuby Immunology) Paperback – January 25, 2013 by Judy Owen (Author), Jenni Punt (Author), Sharon Stranford (Author)

9/30/2016 Hashemi S.M. 3 Clinical Immunology: Principles and Practice (Expert Consult - Online and Print), 4e (Rich, Clinical Immunology) Fundamental Hardcover – December Immunology Hardcover – 26, 2012 by Robert R. December 11, 2012 Rich MD (Author), by William E. Paul (Author) Thomas A Fleisher MD FAAAAI FACAAI (Author), & 4 more Be the first to review this item

9/30/2016 Hashemi S.M. 4 Middleton's 2-Volume Essentials of Clinical Set: Principles and Practice Immunology, Includes Wiley E- Hardcover – November 1, Text Paperback – January 28, 2014 2013 by Helen by Bruce S Bochner MD Chapel (Author), Mansel (Author), A Wesley Burks MD Haeney (Author), Siraj (Author), William W Busse MD Misbah (Author), (Author), & 3 more

9/30/2016 Hashemi S.M. 5 Immunology Books

JJaneway's Immunobiology Cellular and (Immunobiology: Molecular • (Janeway)) Immunology Abul K. Abbas MBBS

Clinical Immunology: Fundamental Principles and Practice Immunology Robert Rich William E. Paul

6 9/30/2016 Hashemi S.M. 7 Well Established

Review article

New Discoveries

8 Hierarchy of Evidence

9/30/2016 Hashemi S.M. 9 9/30/2016 Hashemi S.M. 10 Databases

Original DNA Sequences (Genomes)

Expressed DNA sequences ( = mRNA Sequences = cDNA sequences) Expressed Sequence Tags (ESTs)

Protein Sequences

Protein structures -Experiments -Models

9/30/2016 Literature information 11 9/30/2016 Hashemi S.M. 12 ﺭﺎﺩ ﻝﺳ٩١٠ ﻣﺣﺩﻣ ﺯیﺍﺭﻣ ﻼﺍ ﺍ ﺭﯽﻳ ﺍﺩﺩﺍﻳ ﻧﺑیﻥﻧﺭﺑﻭﻣﺷﮑﺑﻧﺩ ﺍﺭ ﺭﺎ ﺎﮐﯽﺩ ﻡﻧ ﺑﺗ ﻪﺑ ﻑﻭﺧﺧﮏﻼ ﺭﺗﺍﺁ ﻪﺑﺳﻠﺑﻳﻥ"ﺣﺟﺭﺍﻟ یﺩﺍﻟ ﻭﺻﻪﺑ" ﺑ ﺑ ﻔﺻﺭﻩ ﺗﻝﻳ ﮐﺩ ﺭﻣﺭیﺯﻭﺿﻪ ﻪﺯﺩ ﻓﻳﺭ ﻳ ﻪﺎﺎﻭﺍﺑﻥﯽﺭﻧﺑ ﻳﻳﻫ ﺭیﺎﻣﻳ ﻩﺍﺭ ﻣﻧﻭﻩﺁﺍ ﺭﻥﻪﺍ ﺩ ﺍﺍﻭﺭ ﺋﺕﺳﺕﺳﻳ.

/6/910032 mie..MHhSas 31 9/30/2016 Hashemi S.M. 14 ﻥﻳﺍﻧ ﻧﻪﻛﻭﻣﺩ ﺳﺑﻛﻡﻠ ﻪ ﺭﮔﺍ ﺭﻓﺩﻱ ﻣﺯﺍﺭﻳﺎﻱﺑ ﺑﺁﻠﻪﺟ ﺎﻥﺑﻪ ﺭﺩﺑ ﺭﺑﺩ ﺭﺩ ﻭﺭﺑ ﺩﺷ ﺭﺑﺍ ﻳﺕﺁﻳﻥﺩﻧﭘﺍﻭﻣ ﺭﺻﻛﺩﻭ ﻩ ﺭﺑﺍ ﻱﻲﺗﻼﺑﻣﺑ ﺭﺎﻧﻣ ﻭﻡ. ﺩ ﺩﺭ ﻕﺷ ﺭﺩﻱﻪ ﻠﺑﺁ ﺭﺍ ﺍﺯ ﻓ ﺑﺎﻲﻳﺗﺳﻪﺑ ﻥﻳﺍﻭ ﺍﺕﻳﺙﻗﻌﺎﻋﺑ ﺷﻪﺩ ﻛﻪﻳﺎﻣ ﺭﺩﻱ ﻛﮔﺭﻧﺗﻓﺩﻪﻭ ﺑ ﺹﺍﺷﺎﺧ ﻪﻪﺑ ﻭﻁﺭ ﻳﻔﻑﺧﻪﺑ ﺁﻥﻼﺗﺑﻣ ﻭﺑ ﻧﺩﺩﻣ ﻲ ﻟﻡﺎﺳ ﻛﺭﻧﺩﺩ ﺢﻳﻔﻠﺗﻣ ﻲ ﺑﻭ ﺎ ﻥﻳﺍﻳﺩ ﻣﻛﺹﺍ ﺧﻪ ﺷﺗﺢﻳ ﻠﻔﺯﻳﻧﺩﻧﻭ ﻩ ﺷ ﻓﺑﻪ ﻁﻘ ﻛﻲﻳﺷﻑﻠﺧﻔ ﺗﻼﺑﻣ ﺷﺩﻭﺱﻩ ﭘ ﻭﺩﻱ ﺑﺯﺍﻬﺑﺭﮕ ﻳ ﺩ ﺭﺩﺭﺭﺑﺑﺍ ﺁﻥ ﻭﻥﻣ ﺻ ﻣﻧﺩﺑﺎ. ﻥﻳﺍﻛ ﺭﺎ ﺭﺩ ﻭﺍﻝﻳﺍﻫ ﺟﻫﻡﺩﻗﺭﻥﻳﻧ ﺯ ﺩﺎﻥﺗﻠﺳﺭ ﮕﻧﺍﻭﺗ ﺳﻁ «ﻳﻟﺩﻱﻣ ﺎﺭﻱ ﻭﻭ ﻠﺗﻲﺭﺎﺗگﻧﻭﻣ » ﻝﻭﻣﻣﻌ ﺷﺩﻩﻭ ﺎﻬﻟﺎ ﺳ ﻝﺑﻗ ﺍﺯ ﻧژﺗﻣﺭ ﺩﻝﻭﺍ ﮔﺭﻳﺩ ﺩﻩ ﻭﺩﺑ. ﺭﺩ ﺩﺭ ﺑﺳﻣﺎ١٧١۵ﻭﺗﮔﺎﻧ،ﻭﻣﻣ ﺭﺎی ١،ﻣ ﺭﻫﺳﻳﺭﻳﺗﻧﺭ ﻳﺑﺎﻳﺳﻔﮐﺭﻳ ﺑ ﺎ ﺭﺩ ﺑﯽﺭﺭﺩﺎ ﻣﻧﺛﺎ ﻋﻣﺑﻪﺭﻳﺎیﺑ ﺑﺗﻼﺁﻠﻪﯽﺑﻣﻣ ﻭ ﻭ ﺩ ﺷ ﻳﺩﺷﺩﺍ ﺑﺁﻠﻪﻭﺭ ﯽ ﻣ ﺭﮔﺩﺩ. ﻭیﻳ ﻪﺭﺩﮐﺭﺗ ﺵﻭﺑ ﺎﺭ ﯽﺑﺑﺁﻠﻪﻭ ﯽﮐﻳﺩﺁﻧﻧﻳ ﭘﺍﺎﺷﮐ ﯽ ﻣ ﺩﻭﻭﻥ ﭼ ﺭﺑﺍیﭘﺭ ﺳ ﺳﻪ ﺳ یﻭﺩﺎﺧﻟﻪ ﺭﮕﺍﻧﻥ ﻭﺩﺑﻩ ﺍ؛ﺳﺕﺑﻪ ﯽﻧﻭ ﻣﺎﻳﻥ ﺍﻣ ﻁﺍ ﻧﺧﺩﺩﺑﺎﻫﺗﺏﮐ ﺎﻪ ﻧ ﺍ ﺩﻣﻪﻟ یﻧﺎﻣ ﺳﺏ ﻭﺗﺢﻳ ﻠﻘﺟ ﻠﺩیﻝﻭﻥﻣﺧﺑ ﺩﻋﻣ ﺭﻁﺎﻩ ﻭﺍﺧﻫﺩﻭﺩﺑ . ﻭی ١٩ ﺭﺩ ﻣﺱ ﺭﺎ١٧١٨ ﻧﺩﻭﺩﺯﺭﻓﺧ ﺭ ﺍﻭﻳﺕﺑﻓﻣﻘﻭ ﺎ ﺑﻭﻥﺭﻁﺩﺧ ﺧﯽﺻﺷﺗﺢﻳﻣﻭﺎ ﯽﻠﻭﻘﻖ ﻣﻳﺩﮐﻣ ﻪﻭﻓ ﻣﺩﻧﺎ ﺷ ﺭﺩﮕ ﻧﺍﺗﻠﺎﺳﻥ ﺭﻅﻫﻧﺎﻭﻑﺭ ﻁﺍﻌﻣ ﺑ ﻪﯽﺑ ﺑﺁﻠﻪﻭﻣﻳﮐ ﻧﺎ ﻭﺩ ﺑﻪﺑ ﻝ ،ﺎﻧﺁﻝﻥ ﺩﻣ ﻋﻣﻳ ﻪ ﺎ ﯽﺑﻭیﻭﺭﻥ ﻳﮐﻣﺭﺟﻣﻧ ﺩﺯ ﺍﻥ ﻳﺕﮔﻭﻳﻧ ٢ ﺭﻭﻁﺑﺑﻁﻧﻪ ﻭﺩﺎﻠﺟﺍ ﺎﻧﻡﯽﺍ ﻣ ﺭﻳﺩﭘﺫ. ﯽﻧﺩﻧﺵﺯ ﺍﺷﻁ، ﻭﺩﻠﺏﺍ ﺭﻣﺩﺳ ﻪﻭ ﯽ ﺑﯽﺳﻣﻭﺯ ﻪﻥ ﮐ ﻣﻳ ﻪ ﺎﺷﻧﺩﻭ ﻭﻣﻪ ﻫ یﻬﺑﻪ ﻧﺎ ﺯﺟﺁ ﻥﺗﮏ ﻳﮐﻪ ﺑﻪ ﺑﻼ ﻗ ﺑﺗﻼﺁﻭﻠﺩﻪﺑﺑﻩﻣ ﺍ،ﺳﺕ ﻣ ﺗﻼﺑ ﻭﺩﺑﻧﺩﺱﺷﺩﻬﻭ ﭘﻳﺑﺑﻩ ﯽﺳ . ﺎ ﻣ

/6/910032 mie..MHhSas 51 9/30/2016 Hashemi S.M. 16 • ر ژد ﻧﺮﺳﺎل١٧۴٩ ر د ﮫﺮﺷ«ﻠﺑﻛﺮﻲ » ﺷﺪ ﺘﻮﻣﻟﺪنﺘﺴﻠاﮕﺎﻧ . ﻳ ﻧﺰ دﺳﮕﺎﻟﻲردز هدادو ﻚ ﻛ و ﺮﻟﺑدﻲ اﻌﺪﺷحﮔﺎﺮاﺟيﺮدً ﺸﻣ ورﻤﯿﺑﻲﺘﺎر ﺳﺎدﻧ ﭘﺧﺮادﺖآ ﻧﺎﺗﻮﻣﻲ ﺗ ﻪﺤﺑﯿﺼﻞ ﻐﻮل رﻛﺎ ﺷﺪ

ا ﻦ ژﻳﺑﻧﺮﺎ ﻪﻧﯿﺣﺎنن اتوزﯿ اﺸﻨﮔﺒﻛرﻛﻟرﺮ ﺎ ﺎﺎوﺑرﺎوﻪﻛ ﺑﻮدآ ﻨﺷﺧﻮﺎد ﺑﻮدﻧﻣﺘﻘﻌﺪ ﺪ ﯿﺑ ﻪﺑ ﺷﺺﺨﻨﭼﺎﻧﻪﭽ ﺒﻣآﻪ ﻠﺑ يرﻤﯿﺑ ﺎﻪﺑھﮔﺮﺰ دﮕﺮﻳ ﺷﻮ ﮔﻼ دﺘﺒﺎﻣيوآﻪ ﻠﺑيرﻤﺎ ﻼﺘ ﻧاﺨﻮھﺪﺷﺪ . ﻄﺮﺧ ﻧﺎكانﺴ ﻧﺎ ياﺧﻮﺑ ﺮد ﻪﺑﺧﻮ د يرﻤﯿﺑﺎاﻦﻳ ﺴﯿﻧﺖ. • ﯿﺢﻠﻔﺗ ﻣﺎه ر دﺑﺎااﻓﺮدد اﺑﺮﻳ ﻣياﺑﺼﻮﺮﯿﻧﺖرو شﻨﺌ ﻤﻄﻲﻣ اﺗﻮﻨﺪﻧ ﮔ ﺎﻣيوﻲآﻪ ﻠﺑ يرﻤﯿﺑﺎﺮ ﺑﺎﺷﺪآﻪﻠﺑ . ﯿدﻘﻗ ﺎﻣﻮﺿﻮعاﻦ ﻳر دا وبﺑﺎً ﺳوﺎ لﺗﺎ ر ﺑ ﺮﺳوﭘﺧﺮاﻲدﺖ ﺗ ﻪﻖﯿﺤﻘﺑ ١٧٩۶ ﺻ ﻪﺑﺤدﮕﺮﻳﻨﺪﻛ زانآرﻣ آﺎ ﮔ ﻳﺮﻓﺖﺶ ﻢﺗ ﯿﻤوﺼﺷﺪ ﺘﻘﻋﻣﺪﺎﻈ ﺮﻪﻧاﻳﻦ . ﻳﺖ

ﻪﻣﻣرهﺎد١٧٩۶ ژﻧﺮ ﮔ ﺎيوآﻪ ﻠﺑﻣﺎﻪﻳنآ ﻪﻛ ﻪﺑﮔرﻛﺮ اﺎرﯿ ﻨﺒﻟﺖر زيو ﻳاﺟﻮ ﻚدشﺳﺖ ﺑﻮ ﻼﺘﺒﻣيرﻤﯿﺑﺎ وﻟﺷﺪﻲ ﮔﻼ ﺘﺒﺎﻣيوآﻪ ﻠﺑ يرﻤﯿﺑﺎ ﻪﺑ ﺑﻪﭽ ﺴﭘﺮ ﻪﺑ ﮔ ﺮوﻓﺖد زو يدﻪﺑ ﻳﺎﻓﺖﺒﻮﮫدﺑ . ﻪﺘھﻔﻨﺪﭼ ﻛو ﺮد ﻤھﻄﻮﺎﻧ ﯿﺢﻠﻔﺗ ﺑﺴﻪﭘﺮﭽار ﻪ ﺑآﻪ ﻠﺑ ژﻧﻣ ﺮﺎﻪﻳ ﺑﻌﺪ ﻪﻛ ر اﯿﻣﺸﺪﻧ ﻛﻮ ظدﺎكر ھدﺮزا آﻪ ﻠﺑيا ﺸﻧﮔﻮﺎﻪ ﻪﻧﻧ ﯿﭻھ . ﺑﻮرداﺪو

ژﻧﺮ ناﻨﻮﻋ ا رﺗ ﺘﻛﺤ ﺧﻮ ﺎﺖدﺑر رﻛﻲ دﺎﺘﻧﺎﻳﺞ«ﻦﺴﻛا و وتا اﺛﺮﻠﻋﻞ بﺑر ﺎدتﻘﺎﺗﯿﺤﻘ آﻪﻠﺑ ان رو آ ﺷﺨﻛ ﺮﺼدﺎ نﯿﺑﺎﮔﺎوﻦﻳً ﺳر ﺎدل١٧٩٨ ﻤﻧﻮدﺸﺘﺮﻨﻣ . ﺘﻣﻌﺎﻗﺐ ﻣﻘﻪﺎﻟژﻧ ﺮن ﻨﺞﭘآ ﻧﻮﺷﺖﻨﯿﺴنﻛﺎا وﯿﻮﺳر ه رﺑدﯿﻧﺰﺎﻤﻠﻋﻲ. ﺳﺮﻳﻨﻌﯿﺴنﻛﺎﺎا وﯿﻮﺳاﻧﺠمﺎً زاﺑو ﺮيد ﻪﺑ و ﻳﺎﻓﺖﺘﺴﮔ ﺶنﺘﺴﻠاﮕﺎ ﻧ ﻤﺗرم ﺎد ااﻓ ﺮدي ر زﻳدﻨ ﯿﻣﻲﺎﻳﻲﯿﻧﺮيو و رﭘﺬدﻣﻮﻳﺮنﮫش ﺎﺟ ﯿﻧر ﺰد اﺳﺮﺳ ﺮﺑﺧ هﻷ ﺮوﺎﺷﺪيرﺒﺟاﺎ ر اﻗﺮﮔ . ﺮﻤﻓﻋﺖﻞ

رر او طﻮرژ شﻪ ﻧﺮﺑﺧﻮ دهار زااﻦ ﻳ ﻜﻼﺮﺗ ﻧدوشاﮔﺬ ﺷﺖ ﻣرﺮﯿﺘﺧمادﺎ ناﮕررﻳ ﺎ د ا ﻣﻨﺪﻛ ا يزﻧﺪو ّتﺛﺮو ر د ﺳﺎلﺎ١٨٠٢ هد ﻠﺒﻣﻎرراﻈﻮ ﻗدﺪﻧﻨﻣﻲ ﻪﺑنﺘﺴﻠاﮕﺎ ﻧرﭘنﻤﻟﺎﺎ ﻛ ﺮاو ﭘﺧﺮادﺖ ﻪﺑ ﭘﻮرﻧﺪاھﺰ او اهدد ﻪ ﺑدﮕﺮﻳ راھ ﺰﭘﻮﻧﺪ ﺴ ﯿﺑﯿﺖﻧﺰ ﺑ ﻌﺪﺳﺎ لوﻨدﺪﭼ ﺷﺪ .ﮫﺎﺟ ﻧﻳﻲ ﮔژﻧﻣﺮﻌﺮﯿوﻓﺖ ﺮﻄداﺎﻋﻳو ﺪاو ا ا ﻓﻪوﺮﻧﺑﻲ ھيﺎ ﻧ وﺎﻪﺷ توﺘاﻓا رﺨﺎﺎﻓﺖ ازد ﻓﺷﻧﺮﺪ ﺖﻪ ﺳو ﺑﻮد ژﺘﻧﻣﺮﺄھﻞ . ﺳﺎاالو ﻳﻤﻋﻞﺮ ﺳ ﻪﺎ ﺳولزا دﭘاﺘھوﻔﺲﺎ ١٨٢٣ ﮔﺬر دﻠﺑﺷﻛﺮرﻲ ﺖدﺧﻮ دﺧ . ﺎﻪرﻧد

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9/30/2016 Hashemi S.M. 52 early history of B cells

9/30/2016 Hashemi S.M. 53

History of

9/30/2016 Hashemi S.M. 55 History of vaccine

9/30/2016 Hashemi S.M. 56 Vaccine development

9/30/2016 Hashemi S.M. 57 Vaccine development

9/30/2016 Hashemi S.M. 58 9/30/2016 Hashemi S.M. 59 History of Transplantation

9/30/2016 Hashemi S.M. 60 9/30/2016 Hashemi S.M. 61 9/30/2016 Hashemi S.M. 62 How is the Immune Response Initiated? What are the ligands and receptors?

•Infectious-Nonself Model “PAMPs” • Charles Janeway Jr. Cold Spring Harbor Symp. Quant. Bio l. (1989) Detection of conserved molecular patterns (pathogen- associated molecular patterns, PAMPs ) by pattern recognition receptors (PRR). • Danger Model • Polly Metzinger Ann. Rev. Immunol. (1994) .

• Guard Model • Jeffrey Dangl & Jonathan JonesNature (2001) 9/30/2016 Hashemi S.M. 64 65 9/30/2016 Hashemi S.M. 66 9/30/2016 Hashemi S.M. 67 • In recognition of the importance of the discovery • of the DC system, Ralph Steinman was awarded several prestigious prizes, including • the Gairdner Foundation Award in 2003, • the Albert Lasker Award in 2007 • and the Nobel Prize in or Medicine in 2011

9/30/2016 Hashemi S.M. 68 9/30/2016 Hashemi S.M. 69 9/30/2016 Hashemi S.M. 70 Hashemi S.M. 9/30/2016 9/30/2016 Hashemi S.M. 72 • It is very common in the that an important question arises long before the development of experimental strategies or techniques needed to resolve the issue. • Thus, an important but often overlooked approach to discovery is the revisiting of old questions with new techniques. • experiments leading to the T helper type 1 (TH1)-TH2 hypothesis proposed by Tim Mosmann and me in 1986. • The hypothesis was quite simple: two very different subsets of helper T cells exist • by different sets of cytokines secreted after activation and, as a consequence, mediating very different regulatory and effector functions.

9/30/2016 Hashemi S.M. 73 • In 1971, Parish showed that there could be an inverse relationship between humoral and cell-mediated immunity. This work was followed by the demonstration by Parish and Liew in 1972 . that this inverse relationship could be extended to high- and low-zone tolerance • The concept of two-zone antibody tolerance was originally reported in 1964 by Mitchison. However, it was not until 1974 that Liew and Parish showed that T-cell-helping antibody synthesis and T-cell mediating DTH were distinct. • The heterogeneity of CD4 + T cells was further confirmed in 1975 by the demonstration by Marrack and Kappler that -specific TH cells

9/30/2016 Hashemi S.M. 74 Filling in key details

• As that work was proceeding in the Mosmann lab , the Coffman lab next door was trying to determine how IgE antibody responses were regulated . • The two lines of research came together in a dramatic way as soon as we tested supernatants from various TH clones in our assay for IgE roduction. The addition of supernatants containing the TCGF2 activity led to large IgE responses , about 100 times the lower sensitivity of the IgE assay, whereas supernatants containing IL-2 induced no detectable IgE • Also, Tim’s group confirmed experimentally that TH1 cells but not TH2 cells mediated classical delayed-type hypersensitivity reactions • we and many others had begun to address two of the central issues raised by the hypothesis. • First, how do the two TH subsets originate and what controls that process? • And second, what are the mechanisms of the reciprocal inhibition of each subset and its functions by the other? • Over the past 20 years, the most common criticism of the hypothesis has been that it is too simple. Tim and I recognized from the beginning that TH function and differentiation was likely to be more complex, • The real value of the hypothesis, I believe, was not that it was strictly correct or comprehensive but that it provided a clear, testable model of T cell function on which to base future studies .

9/30/2016 Hashemi S.M. 75 9/30/2016 Hashemi S.M. 76 Timeline of immunology

1549 – The earliest account of of () occurs in Wan Quan's (1499–1582) Douzhen Xinfa ( 痘 疹 心).[1] 法 1718 – Smallpox inoculation in realized by West. Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the positive effects of variolation on the native population and had the technique performed on her own children. 1796 – First demonstration of smallpox vaccination ()

1837 – Description of the role of microbes in putrefaction and fermentation (Theodore Schwann)

1838 – Confirmation of the role of yeast in fermentation of sugar to alcohol (Charles Cagniard-Latour)

1840 – Proposal of the (Jakob Henle)

1850 – Demonstration of the contagious nature of puerperal fever (childbed fever) ()

1857-1870 – Confirmation of the role of microbes in fermentation ()

1862 – phagocytosis ()

1867 – Aseptic practice in surgery using carbolic acid ()

1876 – Demonstration that microbes can cause disease-anthrax ()

1877 – Mast cells ()

1878 – Confirmation and popularization of the germ theory of disease (Louis Pasteur) 1880 – 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and used as . Proposed that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to make chicken cholera and anthrax "vaccines" (Louis Pasteur)

9/30/2016 Hashemi S.M. 77 Timeline of immunology

1883 – 1905 – Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear leukocytes) (Elie Metchnikoff)

1885 – Introduction of concept of a "therapeutic vaccination". Report of a live "attenuated" vaccine for rabies (Louis Pasteur).

1888 – Identification of bacterial toxins ( bacillus) (Pierre Roux and )

1888 – Bactericidal action of blood (George Nuttall)

1890 – Demonstration of antibody activity against diphtheria and toxins. Beginning of humoral theory of immunity. () and (Kitasato Shibasaburō)

1891 – Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)

1893 – Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins" (William B. Coley)

1894 – Bacteriolysis (Richard Pfeiffer)

1896 – An antibacterial, heat-labile serum component (complement) is described ()

1900 – Antibody formation theory (Paul Ehrlich)

1901 – blood groups ()

1902 – Immediate hypersensitivity (Paul Portier) and ()

1903 – Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus)

1903 – Opsonization

1905 – "Serum sickness" allergy ( and (Bela Schick)

1909 – Paul Ehrlich proposes "immune surveillance" hypothesis of tumor recognition and eradication

9/30/2016 Hashemi S.M. 78 Timeline of immunology 1911 – 2nd demonstration of filterable agent that caused tumors (Peyton Rous) 1917 – (Karl Landsteiner) 1921 – Cutaneous allergic reactions (Otto Prausnitz and Heinz Küstner) 1924 – Reticuloendothelial system 1938 – Antigen-Antibody binding hypothesis (John Marrack) 1940 – Identification of the Rh (Karl Landsteiner and Alexander Weiner) 1942 – Anaphylaxis (Karl Landsteiner and Merill Chase) 1942 – Adjuvants (Jules Freund and Katherine McDermott) 1944 – hypothesis of allograft rejection 1945 – aka antiglobulin test (AGT) 1946 – identification of mouse MHC (H2) by George Snell and Peter A. Gorer 1948 – antibody production in plasma B cells 1949 – growth of polio virus in tissue culture, neutralization with immune sera, and demonstration of attenuation of neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins) 1951 – vaccine against 1953 – Graft-versus-host disease 1953 – Validation of immunological tolerance hypothesis 1957 – theory (Frank )

19579/30/2016 – Discovery of by Alick Isaacs and Jean Lindenmann[2]Hashemi S.M. 79 Timeline of immunology

1958–1962 – Discovery of human leukocyte antigens ( and others) 1959–1962 – Discovery of antibody structure (independently elucidated by and Rodney Porter) 1959 – Discovery of circulation (James Gowans) 1960 – Discovery of lymphocyte "blastogenic transformation" and proliferation in response to mitogenic lectins- phytohemagglutinin (PHA) (Peter Nowell) 1961-1962 Discovery of involvement in cellular immunity () 1961- Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell) 1963 – Development of the plaque assay for the enumeration of antibody-forming cells in vitro by Niels Jerne and Albert Nordin 1963 Gell and Coombs classification of hypersensitivity 1964-1968 T and cooperation in immune response 1965 – Discovery of lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein) (J. Gordon) and (L.D. MacLean) 1965 – Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock) 1965 – Secretory immunoglobulins 1967 – Identification of IgE as the reaginic antibody (Kimishige Ishizaka) 1968 – Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and Ronald D. Guttmann) 1969 – The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini) 1971 – Peter Perlmann and Eva Engvall at Stockholm University invented ELISA 1972 – Structure of the antibody molecule

9/30/2016 Hashemi S.M. 80 Timeline of immunology

1973 – Dendritic Cells first described by Ralph M. Steinman

1974 - Immune Network Hypothesis (Niels Jerne)

1974 – T-cell restriction to MHC (Rolf Zinkernagel and (Peter C. Doherty)

1975 – Generation of monoclonal (Georges Köhler) and (César Milstein)[3]

1975 - Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein, Hans Wigzell)

1976 – Identification of somatic recombination of immunoglobulin genes ()

1980-1983 – Discovery and characterization of interleukins, 1 and 2 IL-1 IL-2 (, Kendall A. Smith, Tadatsugu Taniguchi)

1983 – Discovery of the T cell antigen receptor TCR (Ellis Reinherz) () and ()[4] (James Allison)

1983 – Discovery of HIV ()

1985-1987 – Identification of genes for the T cell receptor

1986 – vaccine produced by

1986 – Th1 vs Th2 model of function (Timothy Mosmann)

1988 – Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E. Rudd)

1990 – for SCID

1991 – Role of peptide for MHC Class II structure (Scheherazade Sadegh-Nasseri & Ronald N. Germain)

1992- Discovery of transitional B cells (David Allman & Michael Cancro) [5][6]

9/30/2016 Hashemi S.M. 81 Timeline of immunology

1994 – 'Danger' model of immunological tolerance ()

1995 – James P. Allison describes the function of CTLA-4

1995 – Regulatory T cells (Shimon Sakaguchi)

1995 – First Dendritic cell vaccine trial reported by Mukherji et al.

1996 - 1998 – Identification of Toll-like receptors

2000 - Discovery of M1 and M2 macrophage subsets (Charles Mills)[7]

2001 – Discovery of FOXP3 – the gene directing development

2005 – Development of human papillomavirus vaccine ()

2010 - The first autologous cell-based cancer vaccine, PROVENGE, is approved by the FDA for the treatment of metastatic, asymptomatic stage IV prostate cancer. The treatment is marketed at a cost of $93,000 and imparts, on average, only an extra four months of life expectancy. The manufacturer, Dendreon Inc, declares bankruptcy in 2014.

2010 – First immune checkpoint inhibitor, ipilimumab (anti-CTLA-4), is approved by the FDA for treatment of stage IV melanoma

2011 – Carl June reports first successful use of CAR T-cells for the treatment of CD19+ malignancies

2014 – A second class of immune checkpoint inhibitor (anti-PD-1) is approved by the FDA for the treatment of melanoma. Two different drugs, and nivolumab are approved within months of each other.

2016 – Matthew M. Halpert first characterizes role of dendritic cell CTLA-4 in Th-1 immunity

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