First Signs of Rejection

Mixed day today. On one hand, Lillian had a fantastic day. She ate her entire bottles, she had (and absolutely loved) baby food, and even got her pacer wires out. She's extremely happy, and from the outside, she looks perfect. On the other hand, we have a giant cloud over our heads in terms of the first signs that Lillian's rejecting - and they're strong ones too. This is going to get pretty detailed (and that's about the only picture for today), so for all you skimmers, here's the TL:DR version: Lillian gets labs several times a week to check for signs of rejections. Today one of those labs went from "none" to "medium to high". It's only one lab on one day, but it's a really strong sign. Her body is generating a specific type of immune cell designed to attack one of seven unique targets on her donor heart. These cells appeared in massive numbers out of the blue, indicating that these targets (known as antigens) were present earlier, either through a blood transfusion or the tissue graft she has from her Norwood. This sudden appearance is especially telling - it indicates that she was exposed to this target before, thus her body has already developed the cells. In effect, she has effectively been immunized, only this time what she's been immunized against is her new heart.

Long version:
A blood test drawn last night indicates that Lillian has tested positive for an antibody that targets a specific antigen on the donor heart. For those who aren't in medicine, antigens are molecules or substances that the body sees and tries to kill. It does this by producing antibodies for that antigen. Each antibody is specifically targeted for a unique antigen, and will only attack things with that antigen. This process is what happens when you are vaccinated: you're given a weak/killed version of a virus that your body can identify and kill easily, along the way producing antibodies that target that virus. Then, if you were to ever get that virus again, your body would immediately swarm it with antibodies and be done with it.

Before I proceed any further, I need to give some background. This is basically a science lesson that I'm learning too as I'm typing this so I could be wrong at points (if I am, please correct me, I don't want to give out wrong information.).

from Wikipedia

Every normal human, as part of our chromosomes has something known as the major histocompatibility complex (i.e., a section of genes that plays a large part in your immune system). For humans, this resides in a tiny subsection of chromosome 6, and is called the human leukocyte antigen. We classify these antigens into several types, split into two groups. MHC class 1 are antigens which "display" a sub-string of amino acids on the inside of a cell. Class 1 generally targets viral antigens and works by attracting CD8 positive T-Cells (also known as killer T-Cells) which then kill the cells. MHC class 2 antigens (note that I'm not sure why we call these antigens, or why we say HLA antigens, as that's technically redundant) present antigens from the outside of the cell to T-lymphocytes. These cells stimulate helper cells (called T-helper cells) which in turn induce B-cell production, which in turn (it's about to end, trust me) produce antibodies specific to the antigen. HLA antigens A, B and C are all MHC class 1, while the HLA antigens DP, DM, DOA,DOB,DQ, & DR are all MHC class 2 antigens (there are further sub categories, but that's deep enough on this front)

And back to Lillian. Lillian is tested against the A*, Cw*, B*, DRB1*, DR, and DQB1* types (my understanding of this is murky, my source sheet simply says HLA typing, so I don't actually know what we're testing for). We then simply watch her levels of these antigens, in the form of say 51,53 (her level for DR) or 07,45 (her level for B*). In turn, the donor heart has at least 7 HLA antigens that we've identified, so we specifically look for antibodies for those antigens. Up until now (both before the transplant and after) the tests for these antibodies have been negative (which is good), but today, we saw that she has tested positive for antibodies to the donors DR17 antigen. While I don't have context for the number (it could be number of antibodies per some unit of blood, or some percentage), the number associated with the positive result is 68, which we classify as a medium to high level of antibodies *for that specific antigen*.

Now, to clarify, we would normally expect some level of antibodies in Lillian's blood to the donor's antigens. That's simply the natural reaction of the body to the new organ, and in most cases is relatively benign with the anti rejection medicines. In some cases, the body even produces very small levels of the antibodies which act as protection to the heart, in what is known as accommodation (as opposed to rejection). What's concerning for Lillian though, is that it is too early for those low levels to occur. Normally the body will encounter the new organ's antigens over time and produce antibodies some months after transplant. But these antibodies showed up out of no where and in strong numbers... exactly the response we would expect for antibodies targeting a virus that the body has been immunized against.

On top of antibodies targeting the donor's antigens, Lillian's level of CD4 T-cells has also shot up. CD4 T-cells normally act as an amplifier for T-cell receptors, but they also have a side function of interacting directly with MHC class 2 antigens, which includes the DR17 antigen Lillian has reacted to. (as an aside, CD4 levels are one of the things that we use as an indicator of HIV infection. A normal level is in the range of 500-1200x10⁶/L, while a person would undergo treatment at 350, and be diagnosed with AIDS at 200). We would normally want these levels a little lower than average. Lillian's level (the lab result) is C 52, and while I do not know the context of that number, the medical staff at Seattle Children's considered it elevated.

In a sense, her body is gearing up for war. It is recruiting soldiers (the antibodies) and is rapidly increasing the number of targeting tools (the CD4 levels). Lillian isn't in rejection yet, but this is not exactly an encouraging development. In one sense, she would be in rejection when we notice decreased heart function as a result of the body attacking the heart, so if it comes to that we have caught it extremely early (one of the reasons for doing labs constantly).

It may seem depressing at this point, but it's important to put this in perspective too. This is one blood test which detected mid to high levels of one antibody, so she certainly isn't in rejection yet, and even if she enters it, there are things we can do about it. At the same time, the swift arrival of antibodies indicating a pre "vaccination" to the heart is extremely worrying. Lillian's heart failure doctor said that they see this occasionally. However, when asked about the result of the patients who have this sudden offset of antibodies, his response was "they reject".