MHC Genetics and Transplantation

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MHC Genetics and Transplantation
Dr. Prakash Nagarkatti Associate Dean for Basic
Science 733-3180 pnagark_at_uscmed.sc.edu
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Transplantation

• Graft or Transplant Transfer of living cells,
  tissues and organs from one part of the body to
  another or from one individual to another.

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Types of grafts
Autogeneic (survive)
H-2k
Syngeneic (survive)
H-2b
Allogeneic (rejected)
H-2b
Xenogeneic (rejected)
Xenogeneic (rejected)
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Is allograft rejection immunological?
Graft rejected in 14 days
Strain B graft
Strain A
Graft B rejected in 7 days Graft C rejected in
14 days
Strain B
Strain C
Thus, allograft rejection meets two important
properties of immune system----specificity and
memory.
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MHC

• Each species has several histocompatibility (H)
  loci.
• In mice there are over 40 loci, called H-1,
  H-2,H-3,.............H-40.
• If mice differ in any other loci except H-2,
  (such as H-1), graft rejection is slow.
• Thus, H-2 was called MHC and all other loci
  were called minor histocomp. loci

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Human and mouse MHC loci
Human
DP DQ DR B
C A
Complement
Class I MHC
D Region(Class II MHC)
Mouse
Complement
I-Region
K I-A I-E D
Class I MHC
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MHC
Class I MHC
Any nucleated cell
Class I MHC
Class II MHC
B cell
Macrophage
Dendritic
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Polymorphism of MHC antigens (based on phenotype)
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MHC is highly polymorphic

• MHC is highly polymorphic---there are 100s of
  alleles at class I and class II MHC.
• Thus in mouse species the MHC diversity can be
  as high as 1012.
• Thus it is almost impossible to find 2
  individuals having identical MHC.

K
IA?
IA?
IE?
IE?
D
100 X100 X100 X100X100 X100 1012
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Why is MHC polymorphic?

• Lets consider 2 scenarios
• All individuals have the same MHC.
• Each individual has a different MHC.

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Consider that all individuals had same MHC
Virus
MHC
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All individuals had same MHC
Died from grave consequences of a viral
infection
Died from grave consequences of a viral
infection
Died from grave consequences of a viral
infection
Died 1997 due to a viral infection
Virus
MHC
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All individuals have different MHC
Virus
MHC
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All individuals have different MHC
Died in 1997 due to unique MHC
Virus
MHC
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All individuals have different MHC
Died in 1997 due to unique MHC
Virus
MHC
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All individuals have different MHC
Died in 1997 due to unique MHC
Virus
MHC
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MHC polymorphism ensures that all individuals in
a species are not equally susceptible to an
infection
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How does MHC influence allograft rejection?

• Any difference in K, I or D subregion is enough
  to induce graft rejection.
• KbIbDb----KpIpDp---Rejected in 7 days.
• KbIbDb----KpIpDb---Rejected in 15 days.
• KbIbDb----KpIbDb---Rejected in 30 days.

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• Differences in Class II MHC is also sufficient to
  induce graft rejection.
• Example KbIbDb----KbIpDb---Rejected.

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Even within an inbred strain, graft can be
rejected
mouse
Accepted
mouse
mouse
Accepted
mouse
mouse
mouse
Accepted
mouse
mouse
Rejected
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• Y chromosome in males encodes for a minor Ag
  called H-Y. Female mice recognize this as
  foreign and reject the graft.

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Genetics of MHC Ag expression in inbred strains
of mice
X
C3H(H-2k)
DBA/2 (H-2d)
Accept
Accept
Reject
Reject
X
F 1(H-2 k/d)
F 2
H-2k
H-2d
H-2 k/d
H-2 k/d
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The inheritance of MHC genes
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Genetics of Human MHC
Q/R
M/N
M/Q
M/R
N/Q
N/R
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• There is one-in-four chance that HLA is
  compatible between siblings.
• Thus HLA matched siblings are the best donors.

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Who is the best donor?
HLA matched sibling
100
HLA matched unrelated
graft survival
50
2HLA mismatched unrelated
0
1
2
3
4
5
Survival Time
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Tissue Typing(or HLA-typing)
Used to identify HLA molecules on cells
Ab against HLA1
complement
Recipient
Donor
Cells die, appear blue
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Uses of Tissue Typing

• Disputed paternity testing.

A/B
C/D
E/F
A/C, A/D, B/C, B/D
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Uses of Tissue Typing

• Identifying lost babies!

A/B
C/D
E/F
G/H
A/C, A/D, B/C, B/D
E/G, E/H, F/G, F/H
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Uses of Tissue Typing

• Exchange of babies in Toronto

A/B
C/D
E/F
G/H
A/C, A/D, B/C, B/D
E/G, E/H, F/G, F/H
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Uses of Tissue Typing

• Exchange of babies in Toronto

A/B
C/D
E/F
G/H
A/C, A/D, B/C, B/D
E/G, E/H, F/G, F/H
A/C, A/D, B/C, B/D
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Mixed Lymphocyte Reaction
Donor
Recipient
Cell Proliferation
(Irradiate)

• Strong Proliferation---High incompatibility
• Weak proliferation---Low incompatibility
• No proliferation--- 100 compatibility
• Helps to identify any antigenic differences
  between donor and recipient

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Immunologically Privileged Sites

• Sites where incompatible grafts survive
• Ex Hamsters cheek pouch
• Anterior chamber of eye
• Brain
• Lack good lymphatic system
• Cells express FasL

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Immunologically privileged tissue

• Corneal or cartilage grafts---covered with
  Sialomucin which masks the MHC
• Testes express Fas ligand

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Role of FasL in graft rejection
Fas L
Fas
T cell
Testes
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Mechanisms of allograft rejection
CD4
IL-2, IFN-g, TNF
Th1
CTL
CD8
Class II
Class I
Macrophage
Graft cell
ADCC
Almost 10 of our lymphocytes can react against
foreign MHC
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Immunosuppresseive agents
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Immunosuppresseive agents
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Graft versus Host Reaction (GVHR)

• When grafted tissue has mature T cells, they will
  attack host tissue leading to GVHR.
• Major problem for bone marrow transplant.
• Methods to overcome GVHR
• Treat bone marrow to deplete T cells.
• Use autologous bone marrow.
• Use umbilical cord blood.

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GVH disease in humans
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Why is fetus not rejected by the mother?
C/D
A/B
A/C, A/D, B/C, B/D
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Fetus as an allograft
Strain A
Strain B
mate
Immunize with fathers Ags
fetus survives
Skin graft rejected
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Why is fetus not rejected?

• Placenta acts as a barrier or filter.
• It filters anti-MHC Abs.
• Trophoblast---outermost layer of fetal
  tissue---is in direct contact with maternal
  blood.
• Trophoblast expresses weak or no MHC.

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Why is fetus not rejected?

• progesterone---hormone---immunosuppressive.
• Placenta expresses FasL.
• Spontaneous abortions are some times triggered by
  maternal immune response against fetus.

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Ethical aspects

• Baby Fae--- Baboon heart in 1984--- survived
  for 35 days.
• Cloning Human embryos.
• In U.S. each year 3000 patients die and 43,000
  patients are denied heart transplants.
• Declaring patients dead before they are
  completely dead?

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Ethical aspects

• Organs for sale !

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Ethical aspects

• Thanks to mother nature ---MHC is polymorphic.

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Summary

• Why allografts are rejected?
• How to match donor and recipient?
• HLA typing
• MLR
• Who is the best organ donor?
• What drugs are used to prevent graft rejection?
• Why does mother not reject fetus?

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The End