A tissuespecific minor histocompatibility alloantigen that triggers rejection of corneal allografts

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A tissue-specific minor histocompatibility
alloantigen that triggers rejection of corneal
allografts
Zdenka Haskova, Thomas J. Sproule, Derry C.
Roopenian and Bruce R. Ksander Schepens Eye
Research Institute, Boston, MA Jackson
Laboratory, Bar Harbor, ME
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• Background
• Previous studies showed that in orthotopic
  corneal transplantation
• multiple minor histocompatibility alloantigens
  represent stronger
• graft rejection targets than MHC
  alloantigens,
• corneal graft rejection is mediated by CD4 T
  cells
• By contrast, in skin grafts
• stronger transplantation barrier is formed by
  MHC alloantigens,
• the most efficient rejection of skin grafts
  occurs when both CD4
• and CD8 T cells are activated

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• Types of minor H alloantigens
• autosomal - most minor H antigens are encoded
  by automal genes
• mitochondrial
• H-Y
• Minor histocompatibility alloantigens
• large number, however the phenomenon of
  immunodominance
• greatly simplifies immune response

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Immunodominance When grafts are exchanged
between MHC-matched but genetically disparate
individuals in which there are multiple minor H
differences present, the T cell response is NOT
against all of the minor H differences, but is
instead limited to a small number of
immunodominant peptide epitopes. (D.C. Roopenian)
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• In previous corneal grafting studies minor
  transplantation antigens were not defined, and
  corneal grafts were incompatible in multiple
  minor H loci.
• The following experiments were performed in
  donors and recipients that are genetically
  identical except for one defined antigenic
  complex H3.

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• H3 gene complex
• classically defined mouse histocompatibility
  locus
• mapping to chromosome 2 near A coat color
  locus
• contains several loci involved in tissue
  rejection,
• including H3a and H3b
• antigen H3a is presented on MHC Class I to
  CD8 T cells
• (H2-Db-restricted)
• antigen H3b is presented on MHC Class II to
  CD4 T cells

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Question Is the entire H3 antigen complex
immunogenic in both skin and corneal
grafts? Results
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Conclusion H3 antigen complex is immunogenic in
both skin and corneal grafts. Due to immune
privilege corneal grafts survive significantly
better.
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• Question
• Will corneal and skin graft reject if grafted
  only across H3a antigenic barrier?
• antigen H3a is presented on MHC Class I to
  CD8 T cells
• (H2-Db-restricted)

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Results Conclusion H3a minor antigen
disparate corneal grafts enjoy immune privilege
and survive better than skin grafts.
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• Question
• Will corneal and skin graft reject if grafted
  only across H3b antigenic barrier?
• antigen H3b is presented on MHC Class II to
  CD4 T cells

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Genetic map of H3 locus
B10 derived LP derived
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Results Conclusion H3b minor antigen
expressed on corneal grafts was more immunogenic
than if expressed on skin grafts. H3b minor
antigen disparate corneal grafts did not enjoy
immune privilege.
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Question Why H3b minor H antigen incompatible
corneal grafts reject while skin grafts survive?
Although H3b alloantigen did not trigger skin
graft rejection in naive recipients, previous
work in Derry Roopenians laboratory showed that
H3b is expressed in skin grafts. H3b acts as an
immune response gene recipients primed with
H3b and H3a expressing spleen cells are able to
reject subsequent H3a skin grafts faster and in
all recipients, while priming with only H3a
spleen cells results in less than 50 rejection.
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Hypothesis There is a cornea-specific
immunodominant minor H alloantigen within the H3
locus that is expressed in the cornea, but not
the skin
Corneal graft
Skin graft
H3x
H3b
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Probable location of cornea-specific antigen
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Question Will recipients sensitized by R25
corneal graft reject a second R25 cornea more
efficiently?
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Results Recipients of corneal grafts that
accepted first cornea graft were unable to reject
a subsequent corneal graft from the same donor.
By contrast, rejectors of the first corneal graft
uniformly rejected also the second corneal graft.
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Conclusion Those recipients that rejected the
first corneal grafts became sensitized and were
able to reject subsequent corneal grafts in 100
and faster. Recipients that developed tolerance
to the first corneal graft extended immune
privilege also to the subsequent corneal graft.
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Question Will R25 skin grafts sensitize
recipients to reject all subsequent R25 corneal
grafts faster ?
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Results Recipients sensitized with R25 skin graft
rejected a subsequent R25 corneal graft at the
comparable rate as naive animals, and the speed
of rejection was not significantly faster.
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Conclusion Data show that there may be a
cornea-specific antigen in H3b locus. Previous
data from Roopenians laboratory suggest that
this antigen is Class II restricted, and
activates CD4 T cells. Implication There are
tissue specific Class II type minor H antigens in
the cornea that are immunogenic, terminate
immune privilege and act as important targets in
corneal allograft rejection.