Tuesday, June 19, 2012

Peptides used in Experimental Encephalomyelitis Models


Encephalomyelitis (EAE), is a widely used animal model for studies of multiple sclerosis. EAE is induced by stimulating T-cell-mediated immunity to myelin antigens. Active induction of EAE is accomplished by immunization with myelin antigens emulsified in adjuvant. The most common EAE models currently studied use rats and mice. Mice are favored because of the abundance of transgenic and targeted gene-deletion models and the numerous antibodies and immunomodulatory reagents available in this species that can be used to dissect the pathogenic mechanisms in EAE.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Even thought all MS patients exhibit signs of neurological deficit, there is considerable variation in the clinical signs and disease course among individuals. The
pathology in the CNS is very heterogeneous, suggesting that MS may be more accurately described as a syndrome arising from multiple pathogenic pathways, rather than a single disease entity. Mechanistic insights into the complex pathogenesis of MS have relied extensively on animal models of CNS demyelination. Although several different models of demyelinating disease in the CNS exist, the most commonly used animal model for MS is EAE. EAE is induced by stimulating an immune response directed against CNS antigens. The origin of the model dates back to 1925 with the discovery that rabbits immunized with human spinal cord homogenate exhibited spinal cord inflammation and paralysis (referred to as active induction). In the 1930s, Rivers et al. showed that EAE could be induced in primates using multiple injections of emulsions of normal rabbit brain tissue. Subsequently, Paterson demonstrated that transfer of lymph node cells from rats immunized with spinal cord homogenate into naïve animals also induced EAE (referred to as passive induction).

Both multiple sclerosis and EAE are considered to be Th1-mediated autoimmune diseases in which neuroantigen-reactive lymphocytes infiltrate the CNS, mediate the development
of inflammatory lesions, and in some models, trigger the demyelination of axons leading to progressive paralysis. Elevated levels of IL-12 have been reported in humans with progressive multiple sclerosis. Increased frequencies of IL-12–secreting monocytes appear to correlate with active brain lesions detected by magnetic resonance imaging. IL-12 has been functionally implicated in the development of EAE by the observations that αIL-12 (αp70) blocks disease development in mice and IL-12 p40–/– mice are resistant to EAE induction.

Active Induction of EAE with PLP and MBP Protein or Peptide

Experimental autoimmune encephalomyelitis (EAE) can be induced in SJL mice by immunization with proteolipid protein (PLP), myelin basic protein (MBP), or peptides. Peptides used correspond to the immunodominant epitopes of MBP (MBP84-104), MOG (MOG92-106), or PLP (PLP139-151 and PLP178-191). In C57BL/6 mice the disease can be induced by immunization with the peptide corresponding to the immunodominant epitope of MOG (MOG35-55).

SJL Mice Info:  Inbr: F104 (J). Albino. Genet: c, p, rd. Origin: Swiss Webster outbred stock from three sources that were brought to The Jackson Laboratory between 1938 and 1943, and pen-bred until 1955, when sib-mating was started. Although the strain has been developed relatively recently, it has rapidly become widely used owing to the high incidence of reticulum cell sarcomas resembling Hodgkin's disease. General biological data on the strain have been reviewed by Crispens (1973). Carries the pink-eyed dilution gene, p, which is derived from Asian mice of the Mus musculus type (see also strains 129/J, P/J and FS/Ei) (Brilliant et al, 1994).

 Source: http://www.informatics.jax.org/external/festing/mouse/docs/SJL.shtml


TABLE 1:      Murine EAE modelsa. Encephalitogenic Peptides of MBP, PLP, and MOG in Various Inbred Mouse Strains

Mouse strain
MHC
Peptide
Peptide sequence
Peptide origin
Clinical course
PL/J
H-2u
MBPAc1-11
Ac-ASQKRPSQRHG
rat
Classic
B10.PL
H-2u
MBPAc1-9
PLP178-191
MBP35-47
PLP43-64
Ac-ASQKRPSQR
NTWTTCQSIAFPSK
TGILDSIGRFFSG
EKLIETYFSKNYQDYEYLINVI
rat/mouse
mouse
rat/mouse
mouse
Classic
Classic
Classic
Classic
SJL/J
H-2s
PLP139-151
PLP139-151b
PLP178-191
MBP84-104b
MBP89-101
MOG92-106d
PLP57-70
PLP104-117
HCLGKWLGHPDKF
HSLGKWLGHPDKF
NTWTTCQSIAFPSK VHFFKNIVTPRTPPPSQGKGR
VHFFKNIVTPRTP
DEGGYTCFFRDHSYQ
YEYLINVIHAFQYV
KTTICGKGLSATVT
human/mouse human/mouse
mouse
rat
rat ?
mouse
mouse
mouse
Classicc
Classicc
Classicc
Classicc
Classic
Classic
Classic
Classic
C57BL/6
H-2b
MOG35-55
MOG35-55
PLP178-191
MEVGWYRSPFSRVVHLYRNGK MEVGWYRPPFSRVVHLYRNGK
NTWTTCQSIAFPSK
rat/mouse
human
mouse
Classic
Classic
Classic
NOD
H-2g7
MOG35-55 PLP48-70
PLP56-70
MEVGWYRSPFSRVVHLYRNGK TYFSKNYQDYEYLINIHAFQYV
DYEYLINVIHAFQYV
rat/mouse
human/mouse
Classic
Classic
C3H.SW
C3H
H-2b
H-2k
MOG35-55
PLP103-116
MEVGWYRSPFSRVVHLYRNGK
YKTTICGKGLSATV
rat/mouse
Classic
ABH (Biozzi)
H-2dq1
PLP56-70
MOG8-22
DYEYLINVIHAFQYV
PGYPIRALVGDEQED
mouse
rat
Classic
Classic
A.SW
H-2s
MOG92-106d
DEGGYTCFFRDHSYQ
rat
Atypical
C3H/HeJ
H-2k
PLP190-209
PLP215-232
SKTSASIGSLCADARMYGVL
PGKVCGSNLLSICKTAEFQ
human/mouse
human/mouse
Classic or Atypical
Classic or Atypical
CBA/J
H-2k
PLP190-209
PLP215-232
SKTSASIGSLCADARMYGVL
PGKVCGSNLLSICKTAEFQ
human/mouse
human/mouse
Atypical
Atypical
DBA/1
H-2q
MOG79-96d
GKVALRIONVRFSDHGGY
rat
Classic
BALB/cPt
H-2d
PLP178-191
NTWTTCQSIAFPSK
mouse
na
(SJLX C3H/HeJ)F1
H-2s/k
PLP190-209
PLP215-232
SKTSASIGSLCADARMYGVL
PGKVCGSNLLSICKTAEFQ
mouse
na
(SJL X B10.PL) F1
H-2s/q
PLP139-151
PLP178-191
MBPAc1-11
HSLGKWLGHPDKF
NTWTTCQSIAFPSK
Ac-ASQKRPQRHG
mouse
mouse
rat/mouse
na
SWR
H-2q
PLP215-232
PGKVCGSNLLSICKTAEF
na
na
(PL/J X SJL) F1
H-2s/u
MBPAc1-11
PLP43-64
PLP139-151
Ac-ASQKRPQRHG
EKLIETYFSKNYQDYEYLINVI
HSLGKWLGHPDKF
na
na

This table summarizes a variety of murine EAE models that can be actively induced with emphasis on the dominant encephalitogenic epitopes that have been described. This list is not inclusive of all EAE murine models reported in the literature. Strains that are in bold are the most commonly used.
bMultiple peptides within this region are encephalitogenic.
cReported to exhibit relapsing-remitting clinical course.
dPertussis toxin is not required for EAE induction with this strain/antigen combination, but influences the clinical course in A.SW mice.
MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein.

Note 1:  The EAE observed in some of these mice is nonclassical. In (SJL X C3H/HeJ)F1 mice, the disease causes imbalance and axial rotary movement (rotary EAE). In BALB/cPt, mice show lack of balance and forelimb paralysis in the absence of hindlimb paralysis.

Note 2:  Sequences for MBP peptides are based on different species variants of MBP, which have different numbering systems; sequences for PLP and MOG peptides are based on the mouse sequence. The reader is urged to consult the indicated references for more detailed information.
References
Burkhard Becher, Brigit G. Durell, and Randolph J. Noelle; Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 J. Clin. Invest. 110:493–497 (2002).
Brilliant M. H., Ching A., Nakatsu Y., and Eicher E. M. (1994) The original pink-eyed dilution mutation (p) arose in asiatic mice: Implications for the H4 minor histocompatibility antigen, Myod1 regulation and the origin of inbred strains. Genetics 138, 203-211. \par
Crispens C. G. (1973) Some characteristics of strain SJL/JDg mice. Lab. Animal Scie.  23, 408-413. \par

Ingunn M Stromnes & Joan M Goverman; Active induction of experimental allergic encephalomyelitis Nature Protocols 1, 1810 - 1819 (2006)

Stephen D. Miller, William J. Karpus, and Todd Scott Davidson; Experimental Autoimmune Encephalomyelitis in the Mouse Curr Protoc Immunol. 2007 May ; CHAPTER: Unit–15.1. doi:10.1002/0471142735.im1501s77

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