Clinical Immunology Evelien Floor
HC3 Transplantation
HLA and transplantation
HLA stands for human leukocyte antigen. HLA molecules are the biggest difference between individuals
which forms a problem during transplantation. The function of HLA is to present antigens to T cells.
There are two classes of HLA molecules. HLA class I is present on CD8+ T cells and is anchored into the
membrane via one domain (a3), a2 and a1 form the antigen binding cleft. HLA class II is present on
CD4+ T cells and composed of an a and b chain both anchored into the membrane. Those different
chains are encoded by different genes. HLA class I can bind shorter peptides then HLA class II
HLA diversity
The HLA system is so diverse because HLA supports the immune system (T cells) in eliminating
pathogens. To this end, HLA needs to be able to present a broad repertoire of antigens. So, a large
diversity of different HLA molecules within a single individual is essential for a species to
immunologically fight pathogens.
HLA has two important factors: polymorphism and polygeny. Polymorphism means: one gene has
different versions (alleles). Polygeny means: one gene is present in multiple copies on the genome
(duplicates), e.g. there are multiple HLA genes in the genome. For HLA class I there is HLA-A, HLA-B,
and HLA-C. For HLA class II there is HLA-DR (DRB1, DRB3, DRB4, DRB5), HLA-DQ, and HLA-DP. HLA
genes are all located on chromosome 6. HLA class III genes encode for other proteins but are called
HLA class III because they are in proximity of the other HLA genes.
The HLA system contains up to 17.000
variants. The number of identified HLA
alleles increases a lot over time. Most of
the polymorphisms are occurring in the
a1 and b1 domain of the HLA molecule
because that is the peptide binding site.
Peptides are anchored in the HLA molecule: anchor position.
These anchor positions determine which antigens can be
presented by the HLA molecule. Some amino acids are more
important for anchoring than other amino acids. In addition,
a certain amino acid is more determining than another. This
way, diversity in the peptide binding cleft determines
binding of an antigen.
1
, Clinical Immunology Evelien Floor
HLA in transplantation
There are two types of transplantation: solid organ transplantation and hematopoietic stem cell
transplantation (HSCT). The direction of the immune response is different in both of these types. In
case of organ transplantation there only can be graft failure because of rejection of the organ.
However, in case of HSCT there can be rejection but also be graft-versus-host disease in which the
foreign graft cells attack the immune system of the host.
Organ transplantation
The less HLA mismatches between donor and recipient, the better the survival rate. However, it is hard
to find a donor without any HLA mismatches. The aim of HLA diagnostics is to reduce the risk for
rejection with emphasis on the humoral component. Three forms of humoral rejection are:
1. Hyperacute rejection from pre-formed HLA antibodies
2. Acute humoral rejection
3. Chronic humoral rejection
Patients on the waiting list for organ transplantation are screened for multiple things:
• HLA typing
• HLA antibody screening
• (in vitro) cellular screening
o 4 times per year
o Cross matches with a panel of sera of 50 random individuals (to represent the normal
donor population)
o Identification of toxic antibodies
There are two forms of allorecognition in organ transplantation:
1. Direct allorecognition
o Still some donor DCs present in the organ with different HLA molecules. Alloreactive
CD4+ and CD8+ T cells recognize these HLA molecules. The CTLs get activated and kill
the graft cells
o There is no antibody formation
2. Indirect allorecognition
o This mechanism is thought to be more prominent
o Patients’ APCs recognize allogeneic HLA which is taken up and presented as peptides
on HLA-II. CD4+ T cells recognize this peptide and activate B cells. Finally, there is
donor specific antibody production.
o Indirect allorecognition is involved in HLA antibody production
2
HC3 Transplantation
HLA and transplantation
HLA stands for human leukocyte antigen. HLA molecules are the biggest difference between individuals
which forms a problem during transplantation. The function of HLA is to present antigens to T cells.
There are two classes of HLA molecules. HLA class I is present on CD8+ T cells and is anchored into the
membrane via one domain (a3), a2 and a1 form the antigen binding cleft. HLA class II is present on
CD4+ T cells and composed of an a and b chain both anchored into the membrane. Those different
chains are encoded by different genes. HLA class I can bind shorter peptides then HLA class II
HLA diversity
The HLA system is so diverse because HLA supports the immune system (T cells) in eliminating
pathogens. To this end, HLA needs to be able to present a broad repertoire of antigens. So, a large
diversity of different HLA molecules within a single individual is essential for a species to
immunologically fight pathogens.
HLA has two important factors: polymorphism and polygeny. Polymorphism means: one gene has
different versions (alleles). Polygeny means: one gene is present in multiple copies on the genome
(duplicates), e.g. there are multiple HLA genes in the genome. For HLA class I there is HLA-A, HLA-B,
and HLA-C. For HLA class II there is HLA-DR (DRB1, DRB3, DRB4, DRB5), HLA-DQ, and HLA-DP. HLA
genes are all located on chromosome 6. HLA class III genes encode for other proteins but are called
HLA class III because they are in proximity of the other HLA genes.
The HLA system contains up to 17.000
variants. The number of identified HLA
alleles increases a lot over time. Most of
the polymorphisms are occurring in the
a1 and b1 domain of the HLA molecule
because that is the peptide binding site.
Peptides are anchored in the HLA molecule: anchor position.
These anchor positions determine which antigens can be
presented by the HLA molecule. Some amino acids are more
important for anchoring than other amino acids. In addition,
a certain amino acid is more determining than another. This
way, diversity in the peptide binding cleft determines
binding of an antigen.
1
, Clinical Immunology Evelien Floor
HLA in transplantation
There are two types of transplantation: solid organ transplantation and hematopoietic stem cell
transplantation (HSCT). The direction of the immune response is different in both of these types. In
case of organ transplantation there only can be graft failure because of rejection of the organ.
However, in case of HSCT there can be rejection but also be graft-versus-host disease in which the
foreign graft cells attack the immune system of the host.
Organ transplantation
The less HLA mismatches between donor and recipient, the better the survival rate. However, it is hard
to find a donor without any HLA mismatches. The aim of HLA diagnostics is to reduce the risk for
rejection with emphasis on the humoral component. Three forms of humoral rejection are:
1. Hyperacute rejection from pre-formed HLA antibodies
2. Acute humoral rejection
3. Chronic humoral rejection
Patients on the waiting list for organ transplantation are screened for multiple things:
• HLA typing
• HLA antibody screening
• (in vitro) cellular screening
o 4 times per year
o Cross matches with a panel of sera of 50 random individuals (to represent the normal
donor population)
o Identification of toxic antibodies
There are two forms of allorecognition in organ transplantation:
1. Direct allorecognition
o Still some donor DCs present in the organ with different HLA molecules. Alloreactive
CD4+ and CD8+ T cells recognize these HLA molecules. The CTLs get activated and kill
the graft cells
o There is no antibody formation
2. Indirect allorecognition
o This mechanism is thought to be more prominent
o Patients’ APCs recognize allogeneic HLA which is taken up and presented as peptides
on HLA-II. CD4+ T cells recognize this peptide and activate B cells. Finally, there is
donor specific antibody production.
o Indirect allorecognition is involved in HLA antibody production
2
