Question

Organ rejection from organ transplants is least common when donors and receivers are genetically related; As I understand it, this is because the antigens on the surface of the cells of the donated organ need to be unrecognizable as foreign (allorecognition in the case that the T cells mark the donor cells as foreign), requiring a genetic match in the major histocompatibility complex (MHC) on chromosome 6 (in humans). But from what I read, I couldn't determine whether 1) there were other histocompatibility genes outside the MHC, or 2) whether there needed to be an exact match between histocompatibility genes, or whether there was some proportion or threshold that would prevent rejection if met (or whether immune response against the organ is just proportional to the level of histocompatibility).

All of this is said the frame this question: Can localized (to a specific tissue or organ) gene therapy result in allorecognition? I imagine if those edits take place in the MHC, it could clearly cause allorecognition due to antigen difference, but are more histocompatibility genes sprinkled throughout the human genome? And even if there weren't, are there other genetic factors beyond antigen formation that can result in a genetically modified cell being rejected by pre-edit host T cells (aside from those modifications which stop the cell from functioning)

Answer 1

Matching MHC genes reduces the risk of rejection in organ transplants, but no graft is completely rejection-free. Localized gene therapy can result in allorecognition, especially if edits are made in the MHC genes. There may not be histocompatibility genes beyond the MHC, but other genetic factors can contribute to rejection.

Step-by-step explanation:

Although matching all of the MHC genes can lower the risk for rejection, there are additional gene products that also play a role in stimulating responses against grafted tissue. No non-self grafted tissue is likely to completely avoid rejection. The more similar the MHC gene match, the more likely the graft is to be tolerated for a longer time. Most transplant recipients, even those with well-matched tissues, require treatment with immunosuppressant drugs for the rest of their lives.

Localized gene therapy for a specific tissue or organ can result in allorecognition. If the edits take place in the MHC genes, it can cause allorecognition due to antigen differences. Although there may not be other histocompatibility genes sprinkled throughout the human genome, there can be other genetic factors beyond antigen formation that can result in a genetically modified cell being rejected by pre-edit host T cells.