This lay person is trying to get his head around the basic mechanisms of tissue rejection.

A lot of articles talk about T-cells being involve but I'm having difficulty following this. Human tissue is essentially similar between individuals. As I understand it the only cellular membrane protein that is (almost) unique is the major histocompatibility complex (MHC) that is expressed on all nucleated cells.

This means that killer T-cells can't recognise transplant tissue cells because of the MHC mismatch. The only cells that can identify non-self human tissue are the humoral innate immune natural killer cells (NKC) and they do this because they are built to kill anything unless it displays self MHC.

OK so NKC spew out the remains of alien tissue cells, but these residues are surely very similar to any other self cells' internals? How do I move from this view to one that involves the adaptive immune system which requires presentation of cellular fragments to lymphocytes?

  • $\begingroup$ I have just read some recent paper on the interaction between NKCs and dendritic cells (DCs). This would provide a way of activating the adaptive immune system providing the DCs were able to present some non-self material from the digested donor tissue. But apart from MHC what differentiating material is available from a donor tissue cell? $\endgroup$ – adlibber Feb 2 '19 at 11:23

There's a really good paper on this, Moreau et al., worth reading through entirely. The only caveat is it was published in 2013, so as a rapidly evolving field such as immunology we might have more insight now. However, the general concepts remain the same.

The lymphocyte compartment that we generate in our own bodies is modulated so that it isn't autoreactive. In other words, for every antigen a T cell should expect to actually encounter in vivo, the ones that attack and kill self cells are made to undergo apoptosis, the special case of course being autoimmunity, which is a set of diseases.

An organ transplant is what's known as a so-called allograft. The allo- prefix implies that the origin is the same species, but from different individuals. So how do people differ at the molecular level? Well for one, we inherit and develop slight differences to such things as protein sequences, carbohydrate chain moieties, and certain receptor combinations. So, your lymphocyte compartment may be non-autoreactive, but it could be alloreactive because those aren't your signals.

The other thing transplants do is cause damage and inflammation that result in the presence of these patterns that the innate immune system respond to called PAMPs and DAMPs, or molecular patterns associated with pathogens and tissue damage. They also bring along donor immune cells like antigen-presenting cells, resident lymphocytes, granulocytes, etc. It's also a functioning tissue, and so just like any of your own cells, a liver cell is expressing class-I HLA loaded with alloantigens. This can have two effects: graft-versus-host, so you have donor immune cells attacking the recipient, and the rejection which is where your recipient immune cells attack the transplant.

Your immune cells attack the transplant predicated on direct and indirect recognition, and the fact that all that inflammation already has the immune system up in arms. So your lymphocytes recognize an alloantigen on the donor antigen-presenting cell is an example of direct recognition. This can occur in the transplant, and also in the recipient lymph nodes as donor APCs can traffic there on signals in the lymph. Recipient APCs can also pick up on alloantigens from donor cells and active the adaptive immune response classically, which would be an indirect recognition.

The blanket treatment for this seems to be immunosuppressive therapy.

  • $\begingroup$ Many thanks for the response. I get the point re donor antigen rejection but you also mention "your lymphocytes recognize an alloantigen on the donor antigen-presenting cell". My understanding is that recognition can only be achieved when the antigen is presented on self MHC type I protein. According to current thinking killer T-cells will ignore any antigen presented on non-self MHC. This difficulty (perhaps my understanding) is at the heart of my question. I am referring to donor tissue cell rejection here rather than any other donor cellular type. NKCs will do the job of course! $\endgroup$ – adlibber Feb 2 '19 at 10:31
  • $\begingroup$ @adlibber That's a good question on it's own. Here's a fairly recent paper that attempts to expain direct allorecognition: What Is Direct Allorecognition?. What you'll find out, in part, is that's it's own long answer and I'm less informed about that topic. $\endgroup$ – CKM Feb 4 '19 at 15:31
  • $\begingroup$ I think I got from the Direct Allorecognition paper the fact that the differences between donor & recipient MHC II is unimportant during donor dendritic activation of host T cells. If my understanding is correct then when the T cells are presented with donor MHC I fragments the adaptive response is activated. Very interesting re MHC II not being an issue. $\endgroup$ – adlibber Feb 6 '19 at 15:26

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