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1-1. McDevitt, H.O. and Chinitz, A.
Genetic control of the antibody response: Relationship between immune
response and histocompatibility (H-2) type.
Science 163:1207-1208. (1969).
and some antigensSynthetic polypeptide antigens-branched multichain synthetic polypeptides-not defined structures-(T,G)-A-L; (H,G)-A-L; (P,G)-A-L
Michael Sela-Weissman Institute for Sciences, Rehovot, Israel
R
R
R R
R
Poly-L -lysine
Poly-D,L -alanine
R=poly (tyrosine,glutamine acid =poly (histidine,glutamic acid) =poly (proline,glutamic acid)
People and Places• John Humphrey-Mill Hill, UK
– Early pioneer in modern immunology with wide interests
• Brigette(Ita) Askonas-Mill Hill, UK– Emil’s postdoctoral advisor
• Don Shreffler-Wash U-Genetics– H-2 Immunogeneticist
• Jan Klein-US/Germany/US– Immunogeneticist, prolific author, iconoclast
It all began with some rabbits
Sandylop:(Mill Hill)Non-responder to(T,G)-A-L
Himalayan:(Israel)
Responder to(T,G)-A-L
MHC Congenic Mouse Strains1948- George Snell (The Jackson Laboratory)
• Using skin transplantation he examined what he termed “histocompatibility genes” = H genes
• The H gene for antigen II was designated H2, later changed to H-2
• He realized that the first step in the genetic analysis of histocompatibility was the separation and identification of individual genes.
• He therefore generated congenic mouse stains Identified 2 types of loci:
Major (strong) = H-2 Minor (weak) = non-H2
i.e. H-1, H-4, H-Y• Nomenclature- STRAIN.LOCUS (i.e. B10.H-2a or B10.A)
Generation of congenic mouse strains
Backcross generations (n)
Probability of homozygosity
(p)
4 0.875
8 0.992
12 0.999
“Speed congenics” decrease the number ofbackcross generations by typing each chromosome for background strain alleles and selecting mice to breed which have the highest number of background genes.
H-2 Congenic mouse strains
Strain H-2haplotype
Origin ofbackground
MHC
A a A -A.BY b A BrackyuryA.CA f A CaracalA.SW s A SwissBALB/c d BALB/c BALB/cBALB.B b BALB/c C57Bl/10BALB.K k BALB/c AKRB6.AKR-H-2k k C57Bl/6 AKRB6.SJL s C57Bl/6 SJLB10 b C57Bl/10 C57Bl/10B10.A a C57Bl/10 AB10.D2 d C57Bl/10 DBA/2B10.M f C57Bl/10 OutbredB10.BR k C57Bl/10 C57BRB10.SM v C57Bl/10 SMB10.RIII r C57Bl/10 RIIIB10.PL u C57Bl/10 PL/JC3H k C3H C3HC3H.SW b C3H SwissC3H.NB p C3H NBD1.C d DBA/1 BALB/cD1.LP b DBA/1 LPLP.RIII r LP RIII
The forgotten guinea pig
Benacerraf (1963) - Guinea PigsStrain 2 Strain 13
PLL(poly L-lysine) + –
GT(glutamic acid/ tyrosine) – +
Inbred stains of guinea pigs -strain 2 and strain 13 -differ at the I region of MHC
1-2. Zinkernagel, R.M. and Doherty, P.C.
Immunological surveillance against altered self components by sensitised T
lymphocytes in lymphocytic choriomeningitis.
Nature 251:547-548. (1974).
People and Places• Rolf Zinkernagel
– M.D. Switzerland -• Cerottini & Brunner- developed the 51Cr-release assay
– Ph.D. Australian National University (ANU)• Canberra headed by Gordon Ada
– Asst. Professor - Scripps– Professor -U. of Zurich
• Peter Doherty– Veterinarian– Postdoc-Scotland– ANU– Wistar, ANU, St. Jude’s– Australia
1-3. Babbitt, B.P., Allen, P.M., Matsueda, G., Haber, E., and Unanue, E.R.
Binding of immunogenic peptides to Ia histocompatibility molecules.
Nature 317:359-361. (1985).
Ir Genes
• How to explain lack of a response– Hole in the repertoire
• T cells do not exist that are able to respond, involving thymic selection
– Determinant Selection• MHC molecules select which determinants they
can present
Numerous groups had completely failed to find any evidence that antigen
associated directly with MHC molecules
JI 133:2067(84)
Identification of the HEL(46-61)/I-Ak epitope
A single HEL tryptic fragment stimulates HEL specific T cells
Stimulatory fragment identified as 46-61
Allen, Strydom, and Unanue, PNAS 1984