This is to be expected. Any time we do any transplant immunosupressants are given to the recipient for the rest of their life, but this only slows the inevitable. Heart transplants recipients all get accelerated atherosclerosis. Lung transplant recipients all get long term fibrosis. We buy time with these procedures and do everything we can to keep them going, but if you have a transplant, you're in a really bad spot to begin with.
> Any time we do any transplant immunosupressants are given to the recipient for the rest of their life, but this only slows the inevitable.
Is this true that it is inevitable? My understanding, from my girlfriend attending medical school (only M1), is that for many types of transplants, when immunosupressants are taken properly, it is unlikely that the organ will ever be rejected.
For example, only 10-20% of patients who receive a kidney transplant will experience rejection[1].
Even if there is no acute rejection event, long-term accumulation of damage from the host's immune system attacking the graft at a low background level is still very likely. Immune suppression has to walk a tightrope that in addition to being very thin is also constantly moving around. Each time you get sick, if your immune suppression is too aggressive, you might just die. If it's not aggressive enough, the pro-immune signalling generated in response to the infection might override the immune suppression and trigger rejection of the graft. Any other event that triggers or suppresses an immune response also has similar risks associated with it.
It's kind of similar to how diabetes patients need to constantly monitor their blood sugar and manually adjust their insulin levels to compensate, but on a longer time scale (generally weeks to months rather than minutes to hours). But with diabetes, at least you have the potential for almost direct control over your blood sugar levels (by regulating food intake). There is no such direct control for your level of immune activity, nor is there a simple and quick blood test to measure whether immune suppression is at the right level.
In short, anyone with a transplant is walking a wobbly tightrope of immune suppression for the rest of their life, and they sometimes don't even know they've fallen off until they hit the ground.
(Source: I have previously worked in a lab studying transplant rejection and trying to, among other things, develop such a simple and quick blood test: https://www.ncbi.nlm.nih.gov/pubmed/24725967)
“Only 20%” and “unlikely to ever be rejected” are worlds apart.
Modern immunosuppressive therapy for, for instance kidneys, has dropped the five year acute rejection rate from 50% to 20%. About 8-10% in the first year.
You can get a 5% 10-year non-rejection rate only in the most hand-picked groups (adheres to meds, no underlying systemic disease, and no chronic nephropathy). That sub-population exists, but it’s pretty uncommon.
I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before. What is it about the foreign cells that is identified as foreign by the host cells? The cells ought to be remarkably similar. They're human, with the same function/pluripotency using the same protein interactions. So why attack it?
Because it's part of the arms race with pathogens that has been going on for a billion years since multi-cellular life first appeared. Pathogens do lots of very clever things to hide from the immune system, so the immune system is tuned to detect very subtle changes. The body largely operates on zero-trust network models, except for a few locations where the benefit of a too-active immune system has serious consequences to the fitness of the organism. The eyes and the testicles are good examples of that in humans.
Adding to some of the other comments: Leukocytes (immune cells) such as B and T cells will undergo "education" when they are developing. For example, B cells, before being released, will go through something called central tolerance in the bone marrow. If the B cell receptors bind a "self" antigen (markers that are associated with our own cells) while developing, it will go through negative selection and be destroyed. Of course, some B cells that bind self antigens do make it through in rare cases and this is what manifests as an autoimmune disease.
Dendritic cells 'teach' lymphocytes what a foreign invader is, right most of us know that from high school, but here's where it goes beyond me:
>They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.
SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.
>Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.
>"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher Fadi Lakkis from the University of Pittsburgh told Liz Reid at 90.5 WESA.
>Using an elegant positional cloning approach, Dai et al. have identified polymorphisms in the mouse gene encoding signal regulatory protein α (SIRPα) to be key in this innate self-nonself recognition. They show that SIRPα receptor CD47 binds SIRPα variants with distinct affinities and propose this affinity sensing to be the mechanism that triggers dendritic cell maturation, the first step in the initiation of the alloimmune response. Given that the SIRPα gene is also polymorphic in humans, it remains to be seen whether human SIRPα variations influence transplantation success.
It's no one thing, but a combination of factors that allow the immune system to identify and attack foreign cells that have entered the system. Think of it like one of those incredibly stupid algorithms that pass for AI today. Except this algorithm is "trained" over millions of years by the host organism dying when it fails to properly classify hostile foreign biomass. Over that long a time it gets to be pretty good, but not 100% flawless: autoimmune disorders like multiple sclerosis result when the immune system incorrectly attacks the body's own tissues, and allergies result when the immune system overreacts to foreign material, such as food or pollen, entering the body.
My understanding is that most cells in the human body regenerate. What I don't understand is how cells that are part of the transplant regenerate. Do they use the host or the transplanted DNA to regenerate?
> I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before.
The immune system is one of the most complicated and wonderful pieces of biology. It's also scary in the ways that it can malfunction and the challenges it presents to modern medicine.
> What is it about the foreign cells that is identified as foreign by the host cells?
The MHC system is a major determinant of histocompatibility.
MHC is an adaptive immune function used to detect foreign antigen that was evolved as a means to combat intracellular pathogens. This cell-surface machinery collects and presents foreign antigens from inside the cell at the cell surface for discovery by immune cells that come into contact. If something "foreign" is found on the MHC, the immune system targets the cell for deletion and upregulates the immune system for further attack.
The genes that code the MHC proteins vary widely between individuals. This can be beneficial as viruses struggle to evolve in a way that evades all MHCs in a population.
Unfortunately, the MHC proteins are themselves a highly reactive antigen that triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:
If any of your own T-cells match your own MHC, they're killed. Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match. And these proteins are incredibly, incredibly polymorphic:
Search "variability", then multiply the numbers -- you're not going to find an exact match for you anywhere, unless you have an identical twin. This is why donor databases exist. If you can find a match for one of the variants, it reduces the product of these multiples.
It's very hard to find a tissue match.
When you transplant foreign tissue, it's an antigen.
Fun fact: did you know your immune system genes aren't at rest and are actually evolving right now? Your immune cells run stochastic hill climbing. It's wild. Check out somatic recombination:
Probably has some sort of MAC address identifier that can detect whether something if different than the host DNA, but I have no idea nor experience in biology.
There is more in your body than just your cells. We are in the infancy of understanding stuff like this, but my WAG is that donor tissue can be rejected because it contains hostile microorganisms that didn't make the radar of the medical staff for whatever reason.
I recently listened to this podcast. https://news.ycombinator.com/item?id=21051174
It is about widespread fraud in the drug industry. During the interview it was mentioned that some people are seeing organ failure due getting fraudulent drugs from abroad. It is possible that this is not what happened in this case, but it seems plausible.
To anyone who has the time, listen to this podcast. It was really educational and scary, pharmaceuticals fraud is no joke.
*The interview discusses the material in Katherine Eban's book Bottle of Lies.
The human brain is wired to make connections, but it's important to step back and realize the universe of "plausible" explanations are almost infinite.
It is nothing more than rank speculation that these two stories are somehow related. The world is teeming with junk science like this, and it can be dangerous and even fatal. (E.g. anti-vexers). That's why I think it's important to recognize it when you see it, and call it out. Even more-so if you find yourself possibly espousing damaging speculation without a scintilla of evidence.
I wonder how long it will take until growing organs from the recipient's own stem cells is actually viable. There definitely is some interesting research, and it would completely circumvent the problems with the immune system.
This issue is why I started Forever Labs (YCS17). We bank your stem cells. Immunity presents many difficult problems to be solved. I’d rather worry about the therapeutic developments alone rather than add immunity on top of it.
Thanks for this. I had no idea this was the case, and have long operated under the erroneous belief that most transplants basically worked and left the recipient relatively problem-free afterward—well, at least as far as the transplant was concerned. It is odd to learn that transplants are a time-buying exercise.
How much of this is mitigated by donor/recipient compatibility (haplotypes? is that the right word?)? Is there no such thing as a purely compatible donor?
Yes identical twins are fully compatible. The first kidney transplant was done between identical twins and the the recipient lived with no anti-rejection medications for decades from what I recall.
A 100% compatible donor is a identical twin or clone.
Besides the MHC haplotypes which govern large parts of the immune response to ‘self’ there is the actual makeup of the rest of the genetic material which may be presented as antigens and then recognised as foreign
Tarleton, who now lives in Manchester, N.H., told the Boston Globe she has no regrets about the transplant because it dramatically improved her life. She has learned to play the piano and banjo, wrote a memoir and has spoken to many groups about her life. She lost 20 pounds and began walking five miles a week.
“I had such a low quality of life prior to my face transplant. Do I wish it had lasted 10 or 20 years? Of course,” she said.
I was on an email list and a woman who had two lung transplants described some of what she had been through and also asserted she would do it again and had no regrets.
You have to understand these are people who have no other viable options. However bad this is, the alternative is worse.
I wrestle with these questions because I wish we were looking for better answers. I am in no way interested in telling people who have had transplants that they were wrong to choose that for themselves.
But transplants are dramatic, heroic, headline grabbing procedures. Helping people keep their organs functioning so they don't need a transplant has much less capacity to grab headlines and fascinate the public and so on.
We increasingly put our time and effort into really dramatic medical procedures that are very expensive and have a golly, gee whiz factor. I think we are likely largely overlooking better paths that would give a higher quality of life in many cases because they have less razzle dazzle.
There's a pic and it's not so pretty. What's much worse to me is the description of what her husband did to her. Consider skipping this one altogether.
Yeah not good, how can men bring themselves to such violence against women. I am sitting here as I write this looking at my wife and cant for the life of me fathom doing such a ghastly act to her or even a woman that I don't know, no matter what I believed (real or imaginary) their transgressions where against me. I don't know the back story but if he was capable of doing this, she probably left him for good reason as I cant imagine this was the first incident. A person has the right to leave if they feel you are no longer the right person for them, sometimes it happens in pretty shitty ways, but it does not justify physical harm to that person.
I am just left speechless, there really should be a death penalty for intentionally maiming a person to the point that they will live the rest of their life in suffering and sorrow. No one deserves the fate this woman has been left with. I am sorry she will have to endure another transplant.
Yeah, it is an incredibly terrible story. Sometimes in fiction (books, movies, etc) I think how unrealistic some depictions of cruelty can be, but then I read stories like this and remember that fiction rarely captures the actual levels of cruelty people are capable of.
I'm a live and let live, everyone has their own pain and their own story, we all are just doing our best sort of guy... But I want to string that guy up.
I mean, in medicine most "fixes" for harsh problems are temporary; nothing is permanent as in the end we all are going to die sooner or later. There's a good reason to think not in terms of "people cured" but in metrics like QALY (quality-adjusted life years) gained - even if this transplant fails tomorrow, it has given that poor woman 5 years of significantly improved (according to her own experience) life quality, and that was a good and valuable thing to achieve even if it turns out that it can't last.
A lot of us think we are invulnerable when we are young. I had a college friend who died of brain cancer a few years after graduating. I myself had a kidney failure a few years ago and now on dialysis. In the snap of a finger your life can change.
“There are so many unknowns and so many new things we are discovering,” said Dr. Bohdan Pomahac, director of plastic surgery transplantation at Brigham and Women’s and one of Tarleton’s surgeons. Still, he said, “It’s really not realistic to hope faces are going to last (the patient’s) lifetime.”
Readit News
Is this true that it is inevitable? My understanding, from my girlfriend attending medical school (only M1), is that for many types of transplants, when immunosupressants are taken properly, it is unlikely that the organ will ever be rejected.
For example, only 10-20% of patients who receive a kidney transplant will experience rejection[1].
[1] https://columbiasurgery.org/kidney-transplant/organ-rejectio...
It's kind of similar to how diabetes patients need to constantly monitor their blood sugar and manually adjust their insulin levels to compensate, but on a longer time scale (generally weeks to months rather than minutes to hours). But with diabetes, at least you have the potential for almost direct control over your blood sugar levels (by regulating food intake). There is no such direct control for your level of immune activity, nor is there a simple and quick blood test to measure whether immune suppression is at the right level.
In short, anyone with a transplant is walking a wobbly tightrope of immune suppression for the rest of their life, and they sometimes don't even know they've fallen off until they hit the ground.
(Source: I have previously worked in a lab studying transplant rejection and trying to, among other things, develop such a simple and quick blood test: https://www.ncbi.nlm.nih.gov/pubmed/24725967)
Modern immunosuppressive therapy for, for instance kidneys, has dropped the five year acute rejection rate from 50% to 20%. About 8-10% in the first year.
You can get a 5% 10-year non-rejection rate only in the most hand-picked groups (adheres to meds, no underlying systemic disease, and no chronic nephropathy). That sub-population exists, but it’s pretty uncommon.
See, for example, blood types, where giving an A type person B type blood will cause serious issues.
Each human has a largely unique signature of HLAs (https://en.wikipedia.org/wiki/Human_leukocyte_antigen).
Dendritic cells 'teach' lymphocytes what a foreign invader is, right most of us know that from high school, but here's where it goes beyond me:
>They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.
SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.
>Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.
>"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher Fadi Lakkis from the University of Pittsburgh told Liz Reid at 90.5 WESA.
Here's the paper https://immunology.sciencemag.org/content/2/12/eaam6202
This seems to be the relevant bit
>Using an elegant positional cloning approach, Dai et al. have identified polymorphisms in the mouse gene encoding signal regulatory protein α (SIRPα) to be key in this innate self-nonself recognition. They show that SIRPα receptor CD47 binds SIRPα variants with distinct affinities and propose this affinity sensing to be the mechanism that triggers dendritic cell maturation, the first step in the initiation of the alloimmune response. Given that the SIRPα gene is also polymorphic in humans, it remains to be seen whether human SIRPα variations influence transplantation success.
The immune system is one of the most complicated and wonderful pieces of biology. It's also scary in the ways that it can malfunction and the challenges it presents to modern medicine.
> What is it about the foreign cells that is identified as foreign by the host cells?
The MHC system is a major determinant of histocompatibility.
https://en.wikipedia.org/wiki/Major_histocompatibility_compl...
https://en.wikipedia.org/wiki/Human_leukocyte_antigen
https://en.wikipedia.org/wiki/Histocompatibility
MHC is an adaptive immune function used to detect foreign antigen that was evolved as a means to combat intracellular pathogens. This cell-surface machinery collects and presents foreign antigens from inside the cell at the cell surface for discovery by immune cells that come into contact. If something "foreign" is found on the MHC, the immune system targets the cell for deletion and upregulates the immune system for further attack.
The genes that code the MHC proteins vary widely between individuals. This can be beneficial as viruses struggle to evolve in a way that evades all MHCs in a population.
Unfortunately, the MHC proteins are themselves a highly reactive antigen that triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:
https://en.wikipedia.org/wiki/Thymus (search "negative selection").
If any of your own T-cells match your own MHC, they're killed. Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match. And these proteins are incredibly, incredibly polymorphic:
https://en.wikipedia.org/wiki/Human_leukocyte_antigen
Search "variability", then multiply the numbers -- you're not going to find an exact match for you anywhere, unless you have an identical twin. This is why donor databases exist. If you can find a match for one of the variants, it reduces the product of these multiples.
It's very hard to find a tissue match.
When you transplant foreign tissue, it's an antigen.
Fun fact: did you know your immune system genes aren't at rest and are actually evolving right now? Your immune cells run stochastic hill climbing. It's wild. Check out somatic recombination:
https://en.wikipedia.org/wiki/V(D)J_recombination
The immune system is incredibly complicated.
There is more in your body than just your cells. We are in the infancy of understanding stuff like this, but my WAG is that donor tissue can be rejected because it contains hostile microorganisms that didn't make the radar of the medical staff for whatever reason.
*The interview discusses the material in Katherine Eban's book Bottle of Lies.
It is nothing more than rank speculation that these two stories are somehow related. The world is teeming with junk science like this, and it can be dangerous and even fatal. (E.g. anti-vexers). That's why I think it's important to recognize it when you see it, and call it out. Even more-so if you find yourself possibly espousing damaging speculation without a scintilla of evidence.
“I had such a low quality of life prior to my face transplant. Do I wish it had lasted 10 or 20 years? Of course,” she said.
I was on an email list and a woman who had two lung transplants described some of what she had been through and also asserted she would do it again and had no regrets.
You have to understand these are people who have no other viable options. However bad this is, the alternative is worse.
I wrestle with these questions because I wish we were looking for better answers. I am in no way interested in telling people who have had transplants that they were wrong to choose that for themselves.
But transplants are dramatic, heroic, headline grabbing procedures. Helping people keep their organs functioning so they don't need a transplant has much less capacity to grab headlines and fascinate the public and so on.
We increasingly put our time and effort into really dramatic medical procedures that are very expensive and have a golly, gee whiz factor. I think we are likely largely overlooking better paths that would give a higher quality of life in many cases because they have less razzle dazzle.
I'm periodically shocked when I'm reminded of how wide is the spectrum between good and bad.
Are there pictures?
I am just left speechless, there really should be a death penalty for intentionally maiming a person to the point that they will live the rest of their life in suffering and sorrow. No one deserves the fate this woman has been left with. I am sorry she will have to endure another transplant.
If anyone hasn't been through some tragic medical shit in their life, pay attention to that. You'll understand it later.