THE IMMUNE SYSTEM

by stevefredman
  • Tutorial: Our skin and intestinal track create barriers that protect our bodies from a world full of bacteria viruses, and the other microscopic creatures. 
  • Immune cells float through our blood and lymph and identify, imprison, and destroy invaders. 
  • In the process of protecting a body they can unleash an inflammatory attack that is painful and debilitating. 
  • At times defenders mistake good guys for bad guys and attack joints (rheumatoid arthritis), the intestine (Crohn’s), the kidney (lupus) or the nervous system (multiple sclerosis.). 

There are over ten billion B lymphocytes in the blood and lymphatic systems of each human body.  Like a hive of bees, they are an ecosystem.3 Each can identify one and only one unique sequence of alien DNA or RNA.  When a B cell encounters its fated invader it rapidly clones itself, makes a huge number of carbon copies.  Some of the offspring become memory cells.   Most, now called “plasma cells”, fabricate free floating antibodies that attach themselves to the foreign protein, and mark it for destruction. 

Some immune cells are sentinels that recognize and ingest foreign protein and “process” it.   Called dendritic or antigen presenting cells they don’t destroy, they display the distilled protein on their outer membrane in an area called the “MHC complex.” 

The T lymphocyte has  receptors that recognize the offering and grab it.  Some T-lymphocytes exterminate viruses; others destroy malignant cells. 

Macrophages “surround and kill microorganisms and remove dead cells.”  Much as a caterpillar turns into a butterfly, macrophages begin life as monocytes.28

Immune cells communicate and influence one another by secreting small molecules called cytokines.2 Some of these play a role in the inflammation that protects us from invaders.  Others are a major contributor to the pain and damage caused by one of several autoimmune diseases.

We can usually temporarily control immunologic assaults with cortisone derivatives.  To block the inflammatory cytokines physicians are increasingly using monoclonal antibodies. 

TNF—tumor necrosis factor—is a misleading—inappropriate name of the family of cytokines that is the major cause of the pain, swelling and inflammation suffered by people who have any of a number of auto-immune diseases. The name was chosen by researchers who were trying to understand how some malignancies were cured when they were intentionally infected with virulent bacteria.31

Intentionally infect a cancer?   Some doctors had tried it here and there for a few centuries, but it wasn’t studied and promoted before William Coley, a physician at a major New York hospital became a believer.   

An upper “crusty,” Coley could trace his American lineage to the Mayflower era.  He graduated from Harvard Medical School in 1988 and during his apprentice years learned that half the surgical repairs of abdominal hernias in kids didn’t work very long. (Hernias are weak areas the belly wall that intestines can protrude through.). He introduced the European approach, using sutures and sewing and resewing, and he was successful and “admired.”32

He started suspecting that infections can lead to a cure for cancer when he located a man whose malignancy disappeared after he developed erysipelas, a streptococcal infection of his face.  Years later the cancer was still gone.  An influential surgeon Coley decided to infect the throat tumor of an Italian immigrant who couldn’t speak or eat.  Making small incisions in the growth, Coley rubbed streptococcus into the wound.  At one point “the patient became extremely ill and looked like he might die.”  But he survived and the tumor “liquefied.” Coley published a case report and promoted his approach. As head of the bone tumor service at New York hospital he injected streptococcus into 1000 malignant sarcomas. After they were infected  about 10 percent of them regressed and disappeared.29  In subsequent years the drug company Parke-Davis marketed a mixture of two virulent bacteria that could be used to treat cancers.  In 1962 the government clamped down on medications that weren’t proven safe and effective. Coley couldn’t prove his approach worked and Parke-Davis stopped marketing the bacteria.

Decades later a team of researchers in Belgium led by Walter Fiers discovered a cytokine that erradicated human tumors that were planted into laboratory mice.  They named the cytokine family TNF—tumor necrosis factor. 

Researchers have developed antibodies that block TNF cytokines.  The medications they developed are among the most costly and profitable pharmaceuticals of the day.  Humira generated $19.9 billion in 2018.  Enbrel/etanercept had $7.1 billion in revenue.  Remicaid/infliximab-$5.9 billion.

The story of the cytokine TNF and the creation of antibodies that block their action starts in 1980.  A researcher named Hilary Koprowski, “a colorful, prominent Polish-born virologist” patented a process he had used in his research—a method for making monoclonal antibodies.4

  The technique was developed 6 years earlier in Cambridge England by George Kohler and Cesar Milstein.  They won a Nobel Prize for the process, but they didn’t bother to file a patent. 

Their project started when they injected purified protein into a mouse.  One of the lymphocytes floating in the creature’s blood realized the injected amino acid was foreign and it had to be destroyed.  The lymphocyte started cloning, making huge numbers of copies of itself.  The numerous identical lymphocytes all made the same antibody.  Days went by.  Then one of the researchers drew blood from the animal’s spleen.  As expected, a large proportion of the mouse’s lymphocytes were now clones of the original cell, and each of the lymphocytes made the same antibody. So far nothing that happened was exceptional.  

At this point they fused some of the lymphocytes to mouse myeloma cells, malignant plasma cells that keep reproducing and don’t die.  The hybrid they created made and kept making large quantities of one and only one antibody.  .  

As Kohler, a shy, gentle Swiss German immunologist later explained, the fusion approach was new and unique.  “If by blind chance the right lymphocyte, the one producing the antibody against the injected antigen had fused with the myeloma cell and was forming daughter cells that were locked into producing the same pure antibody. …it was a long shot.”  Around Christmas 1974 Kohler added the antigen to the fused cells and went home.  If the experiment worked the antibodies produced by the fused cells would combine with the antigens and they would precipitate.  Halos would form around the cells.  He returned hours later and fearing failure brought his wife along to console him.  They looked in the window, saw the halos and were elated.  “I kissed my wife.  I was all happy.26”

Kohler’s partner, Milstein was a Jewish researcher from Argentina.  His 14 year old father had exited Russia the year before the country became embroiled in the First World War.  His Argentina born mother was the head mistress of a school and encouraged her son to study hard and to go to the University of Buenos Aires.  At one point she helped type his PhD thesis.  Married and a post doc researcher, Milstein spent three years in the 50s working at a lab in Cambridge England. He returned to Argentina in 1961 as head of a university department, but a military coup had taken control of the country.  It conducted a campaign against political dissenters, and Millstein had been a prominent anti – Peron student when he was an undergraduate.  It was also targeting Jews.  Milstein felt unsafe and returned to the lab at Cambridge.

In the 1960s and 70s a number of scientists developed mouse myeloma cells (malignant plasma cells) that could be grown in tissue culture and were “immortal”..They or their progeny survived indefinitely.  Milstein learned how to turn two small myeloma cells into one larger cell.  In 1974 he was joined by Georges Kohler, a Swiss postgraduate researcher who was also interested in fusing myeloma cells.  Together they developed the first “hybridoma”—part lymphocyte—part myeloma cell—the first “factory” that produced monoclonal antibodies.  

With a patent in hand, Koprowski owned the process for making monoclonal antibodies.  Along with an entrepreneur named Michael Wall, he formed a company named Centacor, and they tried to figure out how turn mouse monoclonal antibodies into gold. 

In the summer of 1982 Michael re-met Jan Vilcek, a man who studied cytokines and who worked at a New York hospital.  A Czech researcher, Jan was a 6 year old Jewish kid in 1939 when his country was occupied by Nazi Germany.  During the next few years the Nazis rounded up and killed Jews.  Vilcek wrote that he and his parents survived in a hostile environment because they had “a complicated attitude toward their Jewishness.”  At some point they converted to Catholicism.  Later they moved. Jan’s father joined the underground.  One way or another they managed to avoid the death camps.  After the Second World War Russia took control of Czechoslovakia, and the country became part of the Eastern Bloc.  The Soviet Union and the U.S. feared one another, built nuclear missiles, and created armies that could defend their nation.  Travel between the Soviet Bloc and the West was restricted and immigration forbidden.

Vilcek married and became a virology researcher.  When he was in his 20s, fed up with the Czech Communist government, he wanted to “relocate.”    In 1964 the couple received permission to cross the iron curtain for a three day vacation in Vienna. They traveled by auto.  It was October, still warm, and they brought their heavy winter coats.  When they reached the border and their car was being searched Jan worried that the coats would be a giveaway– that the inspectors would realize that Jan and his wife were trying to escape.  He waited while the border guards “hesitated for the longest minutes of his life before letting them pass.4”   Once across the line that divided the countries they, of course, didn’t go back.  After the couple reached Germany, life was rough, but within a year Vilcek was hired by NYU, New York University.

After spending a number of years studying interferon, one of the body’s cytokines, Vilceck attended a workshop on a poorly understood immune regulator called Tumor Necrosis Factor. 

In 1984 Genentech scientists determined and published the complete amino acid composition of TNF.  They purified the human TNF protein and they gave some of it to NYU.  Vilcek and his colleagues accepted the gift and “felt like kids in a candy store. –what should we try first?” 

The cytokine turned out to play a role in a body’s ability to fight viral infections.  It had so many actions that one of Vilcek’s graduate students quipped “TNF should stand for too numerous functions.” 

Cytokines are groups of special proteins.  They are discharged by immune cells and they act as chemical messengers.   After they are secreted by a cell, cytokines bind to receptors on the surface of other cells and they regulate the immune response.  They can work alone, work together, or they can work against one another.

In the 80s Centacor (still struggling) on a whim, a hope, produced a next generation monoclonal antibody that would block or inactivate TNF.  It was “chimeric”, a protein that was part human and part mouse.  The development took experts at Centacor 6 months and its patent was owned by NYU (an independent private research University) and Centacor.  The antibody didn’t (as Centacor had hoped) help people with sepsis.  But blocking TNF hindered one of the cascades of pro-inflammatory cytokines. It stopped or hindered inflammation.

When London doctors (Feldman and Maini) injected the medication into the swollen inflamed joint of a person with Rheumatoid Arthritis it usually helped.  The effect lasted three months.  A repeat injection was also successful.  In 1993 a physician from Holland used the antibody to treat a desperately ill 12 year old girl with a severe case of Crohn’s disease, a chronic inflammation of the small and sometimes large bowel.  The disease can cause diarrhea, pain, bowel blockage and fistulas, connections between the intestine and the skin or an organ.  The infusion was very effective for 3 months and it helped 8 of 10 additional people with severe Crohn’s.

10 years after the original mouse antibody to TNF was generated in Jan Vilcek’s NYU lab, doctors had a tool that helped them treat a number of auto immune disorders.4  

Part of the research was funded by the NIH (the taxpayer).  Part by Centacor. There was a lot of luck and serendipity along the way.5  Both Centacor and NYU were rewarded.  The FDA approved the drug for use in inflammatory bowel disease (for Crohn’s they say it has a positive effect 60 to 70 percent of the time),–and it can be used for ulcerative colitis, rheumatoid arthritis, ankylosying spondylitis and various manifestations of psoriasis.

In 1999 Johnson and Johnson bought Centacor for $4.9 billion.  Revenues from the drug (per J and J) rose annually between 2009 and 2016—from $4.3 billion in 2009 to $7 billion in 2016.6

Humira—adalimumab,  another antibody that blocks TNF, was created in mice that were genetically modified in embryo;  the animals make antibodies that human bodies think were made by a homo sapiens.  Some of the research on the drug was performed by researchers at the government funded Cambridge Antibody Technology, U.K.   The FDA licensed Humira at the end of 2002.  By 2005 AbbVie, the company that owned it, was selling more than a billion dollars worth a year, and by 2018 it was bringing in close to $20 billion.7

Scientists in many of the world’s labs knew how to make monoclonal antibodies to TNF, but they couldn’t market them until they performed placebo control studies that proved their drug was both safe and effective.  And that was costly, ethically questionable, and medically unnecessary.  Then a new law allowed companies to avoid double blind studies if they  could prove their “new” antibody worked as well as the current one—that it was “biosimilar.”   A provision of the Affordable Care Act, gave the original antibody maker, in this case AbbVie, the exclusive right to sell the monoclonal antibody in the U.S. for 12 years.  At the time the FDA provided exclusivity for other new drugs only lasted 5 yrs.   At the end of the 12 years, as a result of a provision in the act, company lawyers were able to keep biosimilars—the biologic equivalent of generics–off the U.S. market for a few additional years if the claimed that one or several of the drug’s 126 patents were fundamental.  (All the patents are presumably novel, non-obvious, and useful, but some merely protect a step in production or an inactive ingredient.)

Four companies produced effective biosimilars and wanted to steer clear of years of pointless litigation.  In an attempt to market their Humira-like medications, the manufacturers signed an agreement with AbbVie in 2017 and 2018.  It allowed them to market their medications outside the U.S.  AbbVie will retain their $10 billion a year U.S. Humira monopoly until 2023.8

Several cytokine families (including interferons) contain both pro and anti- inflammatory molecules.  Inhibitors are currently available to molecules that belong to one of two cytokine groups:  “TNF—tumor necrosis factor” and “interleukins”.

There are a number of the diseases where the  immune- system goes rogue.  Some destroy joints and organs or bring on fatigue, fever, weight loss and an early death. 

An overly zealous cytokine reaction–sometimes called “cytokine storm” may explain why some severe cases of viral pneumonia kill.  High levels of a number of cytokines were found in the blood of  people with infiltrates in both lungs and low levels of blood oxygen caused by SaRS, MERS, AND COVID 19.33

Some of the cytokine harm is mediated by one of more than 36 known interleukins–“hormones of the immune system”, and pharmaceutical researchers have developed, tested, and marketed humanized monoclonal antibodies that block some of them.27

TRANSPLANTATION

On more than 34,000 occasions in 2017, organs from donors, dead and alive —livers, kidneys, hearts and lungs–were transplanted into the body of someone in the United States–and the immune system was challenged.

We learned organ transplant was possible in 1954 when an identical twin successfully gave his brother a kidney.  That’s as far as it went for decades because we weren’t very good at keeping a body from rejecting someone else’s organ.  Our original attempt to prevent the immune system from destroying foreign tissue, our “three drug anti rejection regimen”, according to Thomas Starzl, “wasn’t very effective or safe.”  

Thomas Starzl is the American who pioneered the effort to replace the diseased liver of one person with a healthy liver from someone who had recently died.  He developed a methodical approach by operating on dogs in his garage.  As a surgical trainee he obtained the poor creatures from the pound and his wife, Barbara, “cared for the animals.”  Eventually Starzl could remove the organ without killing the canine. 

He learned how to deal with the blood flow from the small intetines.  It contained nutrients that don’t normally enter the main circulation until they seep  through the liver and are processed.  Starzl learned that his liver transplants couldn’t accept and process the flow.  They failed when he didn’t shunt blood from the small bowel around the liver.  “After surgery his dogs were normal for almost a week; then they began to reject their new liver.”

In 1961 Starzl became chief of surgery at the Denver VA hospital and used prednisone and immuran to prevent rejection in a few kidneys.  He had a modicum of success, but as late as 1978 “Graft survival was unsatisfactory and patient mortality high.10   Ambitious and perhaps a little too preoccupied by the rapid changes in his craft, Starzl remembered the day in 1976 when his wife of 22 years casually drove him to the airport in a snow storm.  He flew to London to present a research paper and while there received “ambiguous phone calls from his family, and he “knew” he could not return home.  After 22 years of marriage his wife Barbara’s “forbearance had run out.”   In 1990, having spent most of his life transplanting organs and teaching others he had a heart attack and wrote a memoir. in it he mused that every person who receives someone else’s organ starts seeing the world in a different way, and that medicine’s ability to save a life by transplanting an organ is a legitimate miracle. 

In 1967 Christiaan Barnard in South Africa and Norman Shumway at Stanford each transplanted a human heart.  Neither recipient survived for three weeks.  In 1971 Life Magazine’s story of an “era of medical failure” told readers that subsequent to the first two “166 heart transplants were performed and 143 of the recipients died.22” 

The son of a pastor and a church organist, Christiaan Barnard, the surgeon who performed the planet’s first heart transplant, was born in a sheep farming region of South Africa.  As a student at the University of Cape Town he was on scholarship, poor, and had to walk five miles to school each day.  After he graduated from medical school Barnard married, had two children, and practiced medicine for 2 years.  Then, deciding he wanted more from life, he accepted a scholarship to the University of Minnesota and spent 30 months (many without his family) working with some of the first surgeons who repaired heart defects in children.  He watched them work, learned techniques, and often operated the machine that oxygenated the bodies of the children whose hearts werent beating. After he returned to South Africa Barnard and his brother who was also a surgeon operated on 48 dogs and they learned how to transplant a heart.  Then he was introduced to a 53 year old man who had severe heart disease, was bedridden, and who was ready to resume his life or die.  The heart Barnard transplanted came from the body of a 25 year old woman who, as the result of a traffic accident,  was brain dead.  The man who received the woman’s liver, survived surgery.  The operation became front page news.  The transplanted heart worked for 18 days before  the patient developed pneumonia, and died.  Reflecting on the man’s decision Barnard later wrote, “For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water convinced you have a chance to swim to the other side. But you would never accept such odds if there were no lion.”

A second heart transplant recipient lived 18 months.  A few years later effective anti rejection medications hit the market.  By 2001, the year Barnard died, doctors in the U.S. were performing 2,400 transplants each year.  87 percent lived for at least a year and ¾ more than five years.

Barnard became a celebrity, let his hair grow, started wearing suits made by an Italian tailor, dated movie stars, and ended his first marriage.  During his life he performed 75 more heart transplants, created a tissue heart valve, and was married two more times.  His rheumatoid arthritis eventually crippled his hands, and when he was 61 he stopped operating.

A month after Barnard performed the first heart transplant Norman Shumway, a California surgeon transplanted the second human heart.  At the time Shumway had been transplanting dog hearts for 10 years and knew technically what to do.  His patient died within three weeks. 

A member of the high school debate team in Kalamazoo Michigan, Shumway originally planned to go to law school, but he was drafted during the Second World War.  One of the soldiers tested when the government decided they needed more doctors and dentists, Shumway scored high and chose medicine over dentistry.  Assigned to a group of men who received pre-medical training at Baylor University, he was a hospital orderly for 6 months before he went to medical school at Vanderbilt.  He was an air force doctor during the Korean War then joined the multitude at the University of Minnesota who were learning how to correct congenital heart defects.  Unable to get much hands-on training he decided to go into private practice and joined an older doctor.  It was not a fit.  Someone convinced him to come to Stanford University, an institution that didn’t have any doctors with heart surgery experience.  A modest man who was relieved when someone else performed the first heart transplant, Shumway became the chief of cardiothoracic surgery at Stanford in 1965.

In 1983, after the FDA sanctified the use of Cyclosporine, the first drug that allowed foreign organs to survive for years, the transplant scene changed.  In the subsequent decades over 700,000 people in this country lived part of their lives with someone else’s liver, kidney or heart.  Kidneys, on average, lasted 12 to 15 years; livers had a shorter lifespan.  That’s going to change now that hepatitis C (a frequent cause of liver destruction) can almost always be cured.  When a person with hepatitis C was transplanted, the new liver was always infected, and had a relatively brief lifespan.

After a person receives a foreign organ, they (almost always) reject the newcomer if they don’t take an immunosuppressant daily for life.  A few anti rejection drugs are currently available.  There’s a marketplace and competition.

Cyclosporine, the first truly effective anti rejection drug, was developed by Sandoz, a Swiss chemical company that, in the 1800s, manufactured dyes and saccharine.  In 1917 the company hired a chemistry professor, and created a pharmaceutical department.  His group isolated ergot from a corn fungus and turned it into a drug used to treat migraine and to induce labor.

In 1958, the company asked employees to take a plastic bag with them when they went on vacation or business trips, and to periodically gather “soil samples that might contain unique microorganisms.”  They knew Penicillin was part of the juice produced by a mold, and they hoped one of their people would find the next great antibiotic.

John Francois-Borel was a company biologist, and reluctant scientist.  He said he originally wanted to make art and he was very gifted.  But, as he put it, “you know how art pays; I am not the Bohemian type.21“Borel was the man who discovered cyclosporin.  The drug prevented the body from rejecting foreign tissue and revolutionized the field of organ transplants.  Borel collected a handful of earth when visiting a desolate highland plateau in Southern Norway.18 A fungus in his sample of Norwegian dirt produced a metabolite (Cyclosporin) that lowered the immune response of lymphocytes.  It seemed to be relatively safe, and some thought it could potentially become an anti rejection drug.16

In 1976 Borel presented his findings to the British Society of Immunology.   “A small stocky surgeon with a mop of curly black hair (Starzl’s description) who had been working in transplantation since 1959,20” Sir Roy Calne was one of several who “asked Borel for samples”.  Calne used the fungus juice to try to prevent the destruction of organs transplanted in rats and dogs.  The drug’s effect was dramatic. 

By 1973 the Sandoz supply of fungus derived cyclosporine was largely depleted.  Large sums of money (around $250 million,) would be needed to create more, evaluate its anti-rejection potential, develop a drug, and obtain approval from the FDA.  There wasn’t much of an organ transplant market, and the investment didn’t make much sense. But with Borel’s help, Calne presented his findings to decision makers at Sandoz.  “The pharmaceutical company agreed that the drug looked more promising now that there was evidence of its effectiveness.” 

Over time, in addition to performing surgery Calne became a well known artist.  He once wrote that art and surgery “Both require careful planning, skill and technique and familiarity.”

  In the early 1980s Starzl used Cyclosporin successfully on liver transplant recipients.  With his results in hand the FDA fast tracked approval of the medication and in 1983 it became available for use in the U.S.  (Currently made generically by a number of countries Cyclosporine’s wholesale price is not outrageous.24 $106.50 a month in the developing world—GB £121.25 per month in the United Kingdom, and about $172.95 per month in the U.S. (if generic drugs are prescribed.)

Pharma scientists can produce great results.  But to create a truly innovative medication, in addition to money they need a modicum of serendipity, imagination, and stubborn determination.11

The second major, now widely used, anti rejection drug was Tacrolimus (Prograf).  Originally isolated from the “fermented broth of a streptomyces bacteria”, it was discovered and developed in the 1980s by Japanese chemists screening “natural substances in the soil for their anti cancer and anti rejection properties.”   They were working at the Fujisawa Pharmaceutical, a company located at the foot of the Tsukuba Mountain, a green oasis with hiking trails, Shinto shrines, and a good view of Mt. Fuji.   

English scientists tried Tacrolimus in dogs and “declared it too hazardous to test in humans.”  Dr Starzl’s group kept at it; they found the drug kept transplanted organs alive in some animals and “rescued some organs that, despite cyclosporine, were being rejected.” Additional clinical trials “suggested that tacrolimus might be safer and better tolerated than cyclosporine.12  ”  

In renal transplant recipients Prograf led to improved graft and patient survival, and that lead to its routine use in U.S. renal and pancreas transplant recipients.  The FDA made it official in 1994.   Fujisawa later merged with and became Astellas, the world’s 14th largest.17 The year before Prograf had a generic competitor, Astrellas sold up to $2.1 billion dollars worth of the medication.

In 2011 an average transplant of one kidney had a price tag of $260,000.  Combined heart and lung transplants were costing $1.2 million dollars.   The first 180 days of post transplant medications was costing $18,000 to $30,000, and a number of generic immunosuppressive drugs had been marketed:  “(cellcept was approved in 1995.  Mycophenolate mofetil became available in 2008, Tacrolimus in 2009), and sirolimus in 2014,”

It’s claimed that the annual cost of U.S. transplant immunosuppressive therapy averages $10,000 to $14,000.  If true then the 33,000 transplant recipients in 2016 are (directly or indirectly) paying $330 million to $462 million a year.  That becomes $3.3 billion to $4.6 billion over ten years if drug prices don’t rise or fall.13  

In India (where the culture surrounding pharmaceutical prices is quite different from ours), the amount paid for Tacrolimus was slashed 65 percent in 2016.  The average recipient now pays $235 to $314 a month for anti rejection medications.

On October 30, 1972 chronic dialysis and kidney transplant became a Medicare ‘”right.”  If someone receives a kidney transplant (at a cost of hundreds of thousands of dollars) the operation and three years of anti rejection drugs are fully funded by the federal government.  At the end of those years the patient is removed from Medicare, and they have to pay for their own anti rejection drugs.  About 22 % of people on anti rejection medications stop taking them:  because of side effects, high cost, or for other reasons.  When a kidney transplant recipient stops their immunosuppressive drugs they almost always reject their kidney, and they are forced to go back on dialysis or die. This is not theoretical.  It happens.  And it’s a problem.14

Currently, in addition to brain death, patients who have severe brain injuries but who are not “brain dead” can become organ donors if the patient consents by means of an advance directive, or the patient’s family decide that life support should be withdrawn. “To avoid obvious conflicts of interest, neither the surgeon who recovers the organs nor any other personnel involved in transplantation can participate in end-of-life care or the declaration of death.”

Some countries have a system where an appropriate dead person’s organs can be transplanted in another unless the person explicitly objected while he or she was alive and competent.  The U.S. and a number of other countries require specific consent.

Founded in 1984, a private non- profit organ transplant organization (UNOS) under contract with the government, “oversees all organ procurement and transplant programs in the country and makes the rules about who can do transplants and how organs are to be allocated (given) to patients. “

People on dialysis wait their turn and managing the waiting list can be difficult.  My former employer tried to open their own renal transplant center in 2004, but closed the unit and paid a fine because they (allegedly) mismanaged the transfer of their patients records.

 There aren’t enough livers for everyone and the people on the liver transplant list who are closest to death get the first organ of available for a person with the same blood type.  There are rules that limit the use of organs for people who are addicts, alcoholics, or obese.  If someone’s BMI (body mass index) is too high they can’t be transplanted with a “brain death” liver.  One day I was asked to see a middle aged female who drove a fork lift in a warehouse.  She had never been sick before, was muscular and didn’t drink or have hepatitis; but her liver was full of fat and she had developed hepato-renal syndrome.  Her liver disease had caused her kidneys to stop working.  When renal failure is caused by liver failure, dialysis doesn’t work.  She was in trouble and needed a liver transplant.  I explained the problem to the patient.  She said O.K., and I called the transplant intake doctor at the university.  It was Friday afternoon, time to go home, and the woman’s BMI (weight) was too high.  The university doctor was sorry but he had to turn the patient down.   I explained that part of the weight was caused by fluid retention. Her dry weight BMI (body mass index) wasn’t too high.  “No can do”, the University physician explained.

I told the patient.  She cried.  Her sister who was in her room cried, and the sister offered to donate part of her liver.  The patient refused.  She was given infusions of a few drugs and for some reasons during the next few days her kidney function didn’t get worse or better.  I visited her each day and we talked.  When Friday arrived she was still alive, and on a whim I called the hepatologist on call at the university.  There’s a group of liver specialists who accept or refuse referrals.  Each doctor is on call for a week; then a new physician takes over.  I explained the situation to the new intake doctor and she said “no problem.  Send her over.”  The nurse called an ambulance.  The woman got a new liver and she did well. 

When someone “dies” and donates their organs teams of doctors come to their hospital.  Livers and kidneys are removed without dissection, without traumatizing blood vessels. The organs are cooled, and transported (sometime by plane or helicopter) to a hospital where surgeons and recipients are waiting.   

Once outside the body “The heart is most sensitive to lack of blood flow, “and needs to be planted in a body within 4 hours.   Lungs, with appropriate cooling “remain viable for 6 to 8 hours”, livers 12 hours and kidneys 24 to 36 hours. 

A few years back our former neighbor’s son, learning he was a “match”, decided to donate half his liver to an uncle he didn’t know that well.  His mother was a mess.  Donors are screened.  They must be young and healthy.  But the operation is tricky.  The liver has a large and a small lobe.  The small lobe is adequate for a small child whose liver isn’t working.  An adult needs part of the large lobe.  The liver has to be “split” and a significant amount of tissue has to be removed.  Over time some liver will grow back, but it takes months.  If too much of the organ is removed the donor is in trouble.  There are occasional complications, mainly bile leaks.  And one in 200 donors dies.  There are only a few centers in the country that do at least 100 living donor liver transplants a year.  The young man’s mother is pretty cool; she has a strong social conscience.  But this was hard.  Bottom line: he donated, and survived.  And mother and son are doing well.25

  • In the U.S. in 2019: 23,401 kidneys were transplanted as well as
  • 8896 livers, 3551 hearts,  and 2714 lungs
  • 11,900 of the donors were brain or heart dead.         
  • 7397 of the organs came from living donors.      
  • In 2019 over 112,000 Americans were on one of many transplant lists and “The wait for a deceased donor was often 5 or more years.25”

1. Additionally:  Once a virus infects a cell, it uses the unit’s protein-synthesis machinery to synthesize more viral proteins. Some of the new creations are degraded into peptide fragments that either exit the cell or are bound to intracellular MHC molecules.  Viral—MHC complexes then move to the surface of the infected cell where they are recognized by roving T cells that induce cell death, by releasing cytotoxic granules.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997009/

  1. Scientists have divided the cytokines– mostly small proteins –into five families.  (chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.)
  2. https://www.ncbi.nlm.nih.gov/books/NBK26921/
  3. Vilcek Jan, Love and science. 7 stories press.  2016.
  4. http://grantome.com/grant/NIH/R35-CA049731-02
  5. https://www.biopharma-reporter.com/Article/2017/05/31/Janssen-At-least-5-more-years-of-multi-billion-dollar-Remicade-sales
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  16. The Search for Anti-Inflammatory Drugspp 27-63| The History of the Discovery and Development of Cyclosporine (Sandimmune®) by J. F. Borel et.al https://link.springer.com/book/10.1007%2F978-1-4615-9846-6
  17. The Search for Anti-Inflammatory Drugspp 65-104     Discovery and Development of FK506 (Tacrolimus), A Potent Immunosuppressant of Microbial Origin by Michihisa Nishiyama, Shizue Izumi;Masakuni Okuhara https://link.springer.com/chapter/10.1007/978-1-4615-9846-6_3
  18. http://www.discoveriesinmedicine.com/Com-En/Cyclosporine.html
  19. https://web.archive.org/web/20110604225608/http://depts.washington.edu/uweek/archives/1998.08.AUG_20/_article14.html
  20. 190-192  The Puzzle People, by Thomas Starzl; University of Pittsburg Press, 1992.
  21. https://www.washingtonpost.com/archive/lifestyle/wellness/1988/11/15/jean-francois-borels-transplanted-dream/f3a931b9-e1a1-4724-9f08-a85ec4d3e68f/
  22. https://med.stanford.edu/news/all-news/2018/01/50-years-ago-stanford-heart-doctors-made-history.html
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  26. NY Times March 4, 1995 https://timesmachine.nytimes.com/timesmachine/1995/03/04/881995.html?pageNumber=26
    1. Monoclonal antibodies to IL-17 play a role in the joint pain and skin changes of psoriatic arthritis, and a number of other conditions.  Toclizumab and other IL-6 inhibitors are sometimes used in people with rheumatoid arthritis or Still’s disease –“an inflammatory disorder that can be chronic and is characterized by fever, arthritis and rash.23″

31.tnf http://www.vib.be/en/news/Pages/Tumor-Necrosis-Factor-Discovered-Years-Ago.aspx

  1. coley https://www.brmi.online/william-bradley-coley
  2. cytokine storm https://www.sciencedirect.com/science/article/pii/S1359610120300927