HC29: HLA & minor histocompatibility antigens
Allogeneic SCT
There are 2 ways of doing an allogeneic SCT:
- Allogeneic SCT with T-cells present in the cell graft: transplantation of an immune system of a healthy donor with the aim to induce a strong T-cell response against the cancer cells of the patient
- Mature donor T-cells in the stem cell transplant mediate GVL and GVHD
- Systemic immunosuppression is required to suppress GVHD
- Systemic immunosuppression is gradually decreased
- Allogeneic SCT without T-cells present in the cell graft
- No systemic immunosuppression is required
- Consists of 2 steps
- T-cell depletion → no systemic immunosuppression is required
- DLI is necessary: 3-6 months after allogeneic SCT to induce GVL
- The patient is in better condition
- Professional antigen-presenting cells of donor origin
- Less pathogens
- Less inflammatory cytokines
- The T-cell response is weaker → better balance between GVL and GVHD
- These patients do better as a group → lesser GVHD reaction
- The body has time to heal damaged tissue from chemotherapy
- Recipient dendritic cells can be replaced by donor dendritic cells
- These patients do better as a group → lesser GVHD reaction
T-cells in infections
HLA:
HLA molecules are located on chromosome 6. Per chromosome, there are 6 genes which play a role in HLA. Because humans have 2 chromosomes, there are 12 genes in total which play a role. There are 2 types of HLA molecules:
- HLA class I: present intracellular antigens
- HLA-A
- HLA-B
- HLA-C
- HLA class II: present endocytosed antigens
- HLA-DR
- HLA-DQ
- HLA-DP
The HLA groups are located in the peptide binding groove. Only dendritic cells, macrophages and B-cells are capable of HLA-II expression. HLA is highly polymorphic → there are many variants and every different allele has its own name.
Negative selection:
Due to negative selection in the thymus of T-cells which have high affinity for HLA self-complexes, there are no T-cells for processing peptides derived from cellular proteins, otherwise autoimmune reactions would be induced.
T-cells after allogeneic SCT:
Donor T-cells recognize foreign peptide-HLA complexes (allo-antigens). When selecting a matching donor, not all 12 but only 10 genes are taken into account → HLA-DP is usually not taken into account:
- When an unrelated donor (URD) is selected, there usually is a 10/10 match but an HLA-DP mismatch
- When a family donor (sibling donor) is selected, there usually is a 12/12 match with HLA-DP also matching
Therefore, after an unrelated allogeneic SCT, there can be T-cells present in the donor graft which are directed against peptides in mismatched HLA-DP → immune reaction. HLA molecules are major histocompatibility antigens. In case of shared HLA molecules, immune responses against minor histocompatibility antigens can occur.
Minor histocompatibility antigens
A minor histocompatibility antigen (MiHA) can be:
- A polymorphic peptide that differs in amino acid composition between patient and donor
- A polymorphic peptide that is presented on patient cells by HLA surface molecules
- HLA is matched between patient and donor
- A polymorphic peptide presented by HLA on patient cells that is recognized by donor T-cells after allogeneic SCT
Generation:
MiHAs are produced by differences in single nucleotide polymorphisms (SNPs) between patient and donor. There are >10 million SNPs in the human genome. On average, 10.000 SNP differences are present in a patient transplanted with an HLA matched unrelated donor. A small fraction of the SNP differences encode polymorphic HLA-binding peptides on patient cells that can be recognized by donor T-cells after allogeneic SCT → minor histocompatibility antigens.
Minor allele frequency:
Each SNP occurs in the human population with a minor allele frequency (MAF), for example:
- MAF T = 0,135 → the chance that a T is present on a particular gene position is 13,5%
- This makes a minor antigen
- MAF C = 0,865 → the chance that a C is present on a particular gene position is 86,5%
- This makes an allelic variant
With this information, the population frequency can be calculated:
- T/T = 0,135 x 0,135 = 0,02
- C/T = 0,865 x 0,135 = 0,12
- T/C = 0,135 x 0,865 = 0,12
- Total = 0,25 → 25%
The disparity rate is the chance that a patient-donor pair is mismatched for the minor histocompatibility in the right direction → the patient is positive and the donor is negative. If the population frequency of a minor antigen is 0,25, the disparity rate is:
- 0,25 x 0,75 = 0,19 → 19%
Clinical responses:
Minor histocompatibility plays a role in different clinical responses:
- Graft rejection: the patient’s T-cells react to the HLA of cells of donor origin
- GVHD: donor T-cells react to patient cells
- GVL: donor T-cells react to the patient’s leukemic cells
T-cells are the reason for inducing both GVHD and GVL, which can be done by peptides in mismatched HLA-DP and/or minor histocompatibility antigens in matched HLA donors.
For a donor T-cell to engage in GVHD and/or GVL, the donor must not express the minor antigen himself. The patient can be either homozygous or heterozygous expressing this antigen.
Selection of donor T-cells:
Donor T-cells are selected as follows:
- Donor T-cells are taken either from the bone marrow or peripheric blood
- Donor T-cells which selectively react with the patient but not with donor cells are selected by measuring the release of IFN-γ in culture supernatants by ELISA
- Usually immortalized patient and donor EBV-transformed B-cells are used
- Minor histocompatibility antigens are identified
- Molecular method
- Biochemical method
- Genetic method
T-cell frequencies for minor histocompatibility antigens (MiHA) are higher in patients with GVHD. This can be minimalized if the minor histocompatibility antigens which the T-cells react to are only on hematopoietic stem cells → there is a GVL effect and minimal GVHD on healthy patient tissues. Nevertheless, the majority of MiHA are expressed on both leukemic cells and healthy non-hematopoietic tissues. Healthy non-hematopoietic tissues where minor histocompatibility antigens are often expressed are:
- Gut
- Liver
- Skin
- Lung
Only a minority are hematopoietic restricted minor histocompatibility antigens. This is relevant for immunotherapy → the antigens can be used as an anti-tumor peptide because they don’t attack healthy cells.
Immune responses after allogeneic SCT
In short, relevant factors in immune responses after allogeneic SCT are:
- The number of SNP mismatches encoding minor histocompatibility antigens
- The number of minor histocompatibility antigens that can be recognized by donor T-cells
- This is dependent on the repertoire of donor T-cell receptor
- The T-cell frequency for each minor histocompatibility antigen
- GVL is the sum of T-cell frequencies for minor histocompatibility antigens expressed on leukemic cells
- GVHD is the sum of T-cell frequencies for minor histocompatibility antigens expressed on healthy non-hematopoietic tissues
- The tissue distribution of each minor histocompatibility antigen
If a male patient is transplanted with an HLA matched female sibling donor, the entire Y-chromosome is foreign for the donor derived immune system (this problem doesn’t occur the other way around, because male patients also express X-chromosomes). Male patients transplanted with an HLA matched male unrelated donor have mismatched HLA-DP and minor histocompatibility antigens, but have no anti Y-chromosome reaction. Which patient develops GVHD and which patient does not cannot be predicted yet.
Immunotherapy
Minor histocompatibility antigens can be used for immunotherapy:
- Cellular therapy
- Adoptive transfer of donor T-cells for hematopoietic-restricted MiHA after allogeneic SCT
- T-cell receptor gene therapy for in vitro production of MiHA with hematopoietic restricted expression
- Vaccination
Patient or donor DC with hematopoietic-restricted MiHA peptides or mRNA
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Mechanisms of Disease 2 2020/2021 UL
- Mechanisms of Disease 2 HC2: Cancer genetics
- Mechanisms of Disease 2 HC3: Cancer biology
- Mechanisms of disease 2 HC4: Cancer etiology
- Mechanisms of disease 2 HC5: Hereditary aspects of cancer
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- Mechanisms of Disease 2 HC11: General principles: molecular diagnostics
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- Mechanisms of Disease 2 HC18: Biomarkers for early detection of cancer
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- Mechanisms of Disease 2 HC27+28: Allogenic stem cell transplantation and donor lymphocyte infusion I&II
- Mechanisms of Disease 2 HC29: HLA & minor histocompatibility antigens
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- Mechanisms of Disease 2 HC31: Targeted therapy and hematological malignancies
- Mechanisms of Disease 2 HC32+33: Primary hemostasis
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Mechanisms of Disease 2 2020/2021 UL
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