UNDERSTANDING of

                         TRANSPLANT ANTIGENS

An antigen is defined as "any substance that the body regards as foreign or potentially dangerous and against which it produces an antibody"(1).

In 1990, Joseph Murray was joint recipient of the Nobel Prize for Medicine or Physiology. In his acceptance speech stated "The story of the renal transplant program of the Peter Brent Hospital in Boston weaves together three distinct threads: the study of renal disease, the phenomenon of skin grafting in twins, and the development of surgical procedures ultimately leading to the use of chemical immunosuppression"(2).

This section deals with the study of kidney disease, and skin grafting - for information of kidney transplants - see navigation bar on this section; for immunosuppressive drugs - see section on medicines (via site index)

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STUDY of RENAL DISEASE

In the 4th century BC, Hippocrates treated clinical cases of kidney disorders and surgically removed a disease kidney from a human patient(3).

Richard Bright "first observed the altered structure of the kidney of patients who died of dropsical" in 1811(4); and 22 years later, from clinical studies, discovered an association between kidney failure and enlargement of the left side of the heart(5) and noted that if the urine contained albumin then dropsy was caused by kidney failure(6).

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SKIN GRAFTING:

In 800BC, Surgeons in India used skin grafts to reconstruct facial injuries of human patients(7).

Gaspare Tagliacozzi restored the nose with a flap of skin taken from the person`s own arm in 1596AD - a technique still used today(8).

Sancassani reported, in 1731, that Gambacurta publicly demonstrated removing pieces of her own skin, replaced this, and the tissue lived(9); and 15 years later, Garengeot successfully regrafted skin into injured soldiers(10).

It was not until 1779, that John Hunter presented his observations of a freemartin (sterile female of male-female twin pair of cattle) to the Royal Society of London - preceded by the Ancient Greeks and Romans who had described this(11).

In 1804, Baronio removed two pieces of skin from a ram, and after being separated for 18 minutes, was grafted and healed, but when he grafted skin between a cow and a mare, he failed(12). Almost 60 years later, in 1863. Paul Bert tried replicating Baronio`s experiments and failed. He tried grafting skin from rats into guinea pigs and failed. He was sceptical of reports of successful allografts - from one person to another(13) -  no doubt because of the failure in animal experiments, whereas had he studied medical history, he would have been aware of the clinical successes spanning centuries.

Meannwhile, in 1823. Bunger successfully reconstructed part of a woman`s nose with a graft from the thigh(14).

In 1869, Reverdin grafted skin from one person to another; but despite this clinical achievement he turned to animal experiments and reported in 1872 on grafts between different species - xenografts(15).

Skin grafts to treat human burns victims were reported - in 1888, by Ivanova who successfully grafted skin from an unborn infant onto a badly burned human patient; and in 1896 by Purchas who treated a burned patient with skin from a living donor(15).

In 1912, Schone suggested that when allografts were unsuccessful, this was due to a form of immune response which he called `transplantationsimunitat`; and two years later, Lexer thought an immune factor was involved if grafts did not take(15). In 1924, Emile Holman reported on two cases of repeat skin grafting in children. From these clinical cases, Holman concluded "It is highly suggestive that the destroying agent is specific for each set of grafts, and it seems plausible to suppose, therefore, that each group of grafts develops its own antibody which is responsible for the disappearance of the new epidermis [of the skin]. Our observations also prompt us to question very strongly the value and wisdom of ever attempting isografts [i.e. allografts] when there is skin available for autografts"(16). Holman`s clinical observations were not readily accepted until Medawar`s clinical findings in 1943(17).

KM Bauer found, in 1927, that rejection does not occur when skin was grafted from one monozygous (identical) twin to another(18).

In 1943, Peter Medawar and T Gibson reported on "The fate of skin homografts in [hu]man[s]". Clinical observations of a patient whose burns were treated with a skin graft showed a second homograft from the same donor rejected quicker than the first(19) - implying the rejection process was an immunological or allergic process that might, potentially, be manipulated(20). A year later, the British government set up a research program to find a suitable method for covering skin of children who had been badly burned in the bombing; and, at  the Government behest, Medawar began animal experiments(21) - grafting skin between rabbits, which in 7-10 days developed cellular filtrate destroying grafted skin(22); and spent almost a year trying to prevent skin from white mice being rejected when grafted on to the backs of brown mice(22). In 1951, Medawar and RE Billingham were asked to devise a foolproof method of distinguishing dizygotic [non-identical] and monozygotic [identical] twins, which they attempted by examining cattle - and failed. Medawar said "In the outcome it proved impossible to distinguish between the two lines of twins by skin grafting", but Medawar did find dizygotic cattle would accept skin grafts from each other and that tolerance was specific. Skin grafted from third-parties was rejected(23) - preceded by his own clinical work.

Meanwhile others had been experimenting with freemartin cattle. F R Lillie, in 1917, dissected placenta of several pairs of freemartin cattle and noted placental intermingling of blood between different sexes of twins(24); and in 1945, RD Owen noted the consequences of tolerance of placental inter-mingling of blood in freemartin cattle. Murray reported 47 years later, these experiments were "not applicable to the clinical situation"(25).

In 1992, Sir Michael Woodruff, in a discussion at an RDS conference on "Animal Experimentation and the Future of Medical Research", stated "I remember Peter Medawar once saying that he saw no application clinically of research in his laboratory and elsewhere on transplantation and immunological tolerance"(26).

refs

1. Martin,EA. Concise Medical Dictionary. 4th ed. Oxford Uni Press. 194

2. Murray,JE. Science. vol 256. 1992.

3. Thornton,J. Principle Claims on Behalf of Vivisection. NVAS. 1901.

4. Bright,R. Medical Cases. vol 1. 1830s.

5. Bright,R. London Medical gazette. vol 12. 1833.

6. Bright,R. Medical Cases. vol 1. 1830s.

7. Mesna,GT. History of Plastic Surgery. cited on www.uslink.net

8. Tagliacozzi,G. De curtorum chirugia per insistionem Venice. 1596.

9. Plastic Surgery Resource Council website www.ps-rc.org

10. TransWeb website www.transweb.org

11. Murray,JE. Science. vol 256. 1992.

12. Plastic Surgery Resource Council website www.ps-rc.org

13. Rapaport,FT. Dausset,J[eds]. Human Transplantation. Grune & Stratton. 1968.

14. Bunger,C. J der Chirurgie unde Augenheilkunde. 1823.

15. Rapaport,FT. Dausset,J[eds]. Human Transplantation. Grune & Stratton. 1968.

16. Holman,E. Surg Gynaec, Obstet. vol 38. 1924.

17. Rapaport,FT. Dausset,J[eds]. Human Transplantation. Grune & Stratton. 1968.

18. King,RC. Stanford,WD. A Dictionary of Genetics. Oxford Uni Press. 1990.

19. Gibson,T. Medawar,P. J Anatomy. vol 77. 1943.

20. Murray,JE. Science. vol 256. 1992.

21. Acierno,L. History of Cardiology. Parthenon Pub Group. 1994.

22. Medawar,P. J of Anatomy. vol 78. 1944.

23. Medawar,P. Nobel Prize acceptance speech. 12 Dec 1960. 

24. Murray,JE. Science. vol 256. 1992.

25. ibid.

26. Woodruff,Sir M. in Botting,JH [ed]. Animal Experimentation and the Future of Medical Research. Portland Press. 1992.