Special Issue: Immunobiology of Transplantation
Transplant Surgeons can Xenograft Kidneys from
untreated Pigs without Rejection
Duncan D Adams*
Faculty of Medicine, University of Otago, Dunedin, New Zealand
Duncan D Adams, Faculty of Medicine, University of Otago, Dunedin, New Zealand, Tel: +64-3-4877989; E-mail:
Received: January 18, 2015; Accepted: March 04, 2015; Published: March 10, 2015
The histocompatibility system exists for defence against
viruses. It is responsible for the rejection of allograft. The immune
system attempts to counter the explosive speed of viral replication
by directing the defensive immune attack by cytotoxic T cells on
to histocompatibility antigens on the infected cell’s surface. This
enables destruction of the virus factories before the cytotoxic T cells
are swamped by the myriad numbers of new virions, a thousand
coming from each infected cell every 10 hours.
The histocompatibility system mistakes alloantigen on grafts
for virus-infected host cells that need swift destruction. For surgical
transplantation, Henry Kaplan discovered that immune ablation
of the recipient followed by inoculation with donor bone marrow
prevents rejection of allogeneic grafts. Sykes has improved Kaplan’s
technique by adding recipient bone marrow cells to the donor ones
injected for reconstitution of the recipient after immune ablation.
Kaplan’s technique, used on untreated pigs, should be the standard
procedure for transplantation.
Keywords: The histocompatibility system; Virus infection; Graft
rejection; Transplantation; Use of allogeneic and autologous bone
Oncologists, wishing to study tumours by transplanting them from
their source to another laboratory animal, found that the tumours were
rejected. Medawar  observed that the rejection of foreign skin grafts on
a woman was accelerated on the second occasion, correctly concluding
that an immunological process was involved.
In 1952 the first successful kidney transplant was performed
between identical twins , demonstrating the genetic basis of rejection.
The genes involved will be described below.
The Histocompatibility System
To emulate identical twins for acceptance of foreign grafts, oncologists
used brother-sister mating of rodents to produce inbred strains. This
led to discovery of the histocompatibility (tissue compatibility) system,
governed by a major genetic complex, named the major histocompatibility
complex (MHC) . These genes code for surface antigens on all nucleated
cells. The MHC is present in all species of vertebrates, including man. Why
does it exist?
Functions of the MHC
The MHC does not exist to frustrate Transplant Surgeons. It is essential for survival of virus infections, and protects, imperfectly,
against autoimmune disease . In a famous experiment Zinkernagel and
Doherty  found that a cell infected by a virus extrudes a viral peptide
on to its surface histocompatibility antigens, where it can be attacked by
a complementary cytotoxic T cell clone, if one exists. As shown in Tables
1, the explosive speed of viral replication necessitates swift destruction
of the virus factories that the infected cells become, with 1,000 virions
emerging from each infected cell every 10 hours  and each new virion
infecting another host cell. The histocompatibility antigens, on every
nucleated host cell, present the extruded viral peptide to cytotoxic T
cells, which places the immune reaction on the cell surface, enabling
destruction of the virus factories before the myriad of virions swamp the
cytotoxic T cells and kill the host.
Mechanism of Immune Tolerance
Parents can react to each other’s histocompatibility antigens. They
impart to their offspring all the genes necessary for this. Therefore, some
mechanism must prevent reaction with self histocompatibility antigens
. Burnet  proposed that immunocytes in the foetus are deleted by
contact with complementary antigen.
Nossal , with superb technology, showed that the switch from
deletion to reactivity is not a stage in the life of an animal, but a stage
in the life of every developing lymphocyte. This explains the continuing
influence of histocompatibility antigens on the immune repertoire.
Confusing sub-maximal immune response with tolerance, Nossal failed
to appreciate his discovery.
Henry Kaplan, a radiotherapist and researcher, who revolutionised
treatment of Hodgkin’s disease , found that animals can be made
haematological chimeras  by total lymphoid irradiation followed by
inoculation with allogeneic bone marrow, after which they will accept
allogeneic skin, heart and bone marrow grafts from the donor of the bone
Clinical achievement of graft-tolerant and hosttolerant
In 2008, Alexander, et al.  brilliantly saved the life of a girl
with liver failure from acute fulminant viral hepatitis. After receiving a
mismatched liver allograft, and ingenious treatments, she eventually
became a haematopoietic chimera, completely tolerant of her mismatched
Table 1: The race between virus and cytotoxic T cell .
Cytotoxic T cell
2 T cells
Virion/T cell ratio:
1 x 1,0002.4
106 x 21.3
2.5 x 1014
106 x 6.3
4 x 1021
106 x 1.6
The result: The virus wins, the patient dies.
Cytotoxic T cell clones need to be
1. Large, preformed , no time for expansion.
2. Specific for conjoint virus-MHC antigenic target , so as not to be
muffled by the myriad numbers of free virions.
The procedure for regularly achieving the needed graft-tolerant, host-tolerant chimera is clearly performance of immune ablation of the
graft recipient, followed by inoculation with both autologous and donor
bone marrow, before performing the allo-transplantation.
Improvement of Transplantation
Megan Sykes  describes Kaplan’s procedure as induction of
Full Chimerism. For successful transplantation in rodents, she found
it inferior to induction of mixed Chimerism, in which Immuno-ablation
of the recipient is followed by reconstitution with bone marrow cells
from the graft recipient (autologous) as well as from the graft donor
(allogeneic). Use of this protocol should enable xenografting from pigs,
offering instant and unlimited supply of grafts for man.
False fear of pig tissues now gone
A long–standing fear that pig grafts would introduce dangerous
retroviruses into man has now been allayed . This has led to the
establishment of many companies attempting to modify pigs to prevent
rejection problems .
Unmodified pigs can be used
In the light of Kaplan’s great discovery that after immune ablation of
the recipient, infusion of donor bone marrow cells makes the recipient a
haematological chimera, tolerant of host and donor tissues, completely
unmodified pigs can be safely used for xenografting kidneys and other
organs into man . Application of xenografting from pigs is needed
urgently, and will be a major advance on current HLA-matched human
organ grafting, with need for long periods of dialysis while awaiting
availability of an HLA matched donor.
I am indebted to Pro-Vice Chancellor Peter Crampton for
administrative support and encouragement.
- Gibson T, Medawar PB. The fate of skin homografts in man. J Anat.
1943; 77(4): 299-310.4.
- Hume DM, Merrill JP, Miller BF. Homologous transplantation of the
human kidney. J Clin Invest 1952; 31: 640.
- Margulies DH, The major histocompatibility complex. In Paul
WE, editors Fundamental Immunology. 4th ed. Lippincot- Raven,
Philadelphia; 1999. 263-286.
- Adams DD. Protection from autoimmune disease as the third function
of the major histocompatibility gene complex. Lancet 1987; 2(8553):
- Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated
cytotoxicity in lymphocytic choriomeningitis within a syngeneic or
semi-allogeneic system. Nature 1974; 248(5450): 701-702.
- Fenner F, White DO. Medical Virology. 4th Ed. Academic Press.
- Simonsen N. On the nature and measurement of antigenic strength.
Transplant Rev. 1970; 3: 22-35.
- Davies TF. Autoimmune Endocrine Disease. New York; Wiley; 1983.
- Burnet FM. The clonal selection theory of acquired immunity.
Cambridge University Press. London. 1959.
- Nossal JG, Pike B. Evidence for the clonal abortion theory of B
lymphocyte tolerance. J Exp Med 1975; 141(4): 904-917.
- Kaplan HS. Hodgkin’s disease: unfolding concepts concerning its
nature, management and prognosis. Cancer. 1980; 45(10): 2439-
- Slavin S, Reitz B, Bieber CP, Kaplan HS, Strober S. Transplantation
tolerance in adult rats using total lymphoid irradiation: permanent
survival of skin, heart and marrow allografts. J Exp Med. 1978;
- Alexander SI, Smith N, Hu M, et al. Chimerism and tolerance in a
recipient of a deceased-donor liver transplant. N Engl J Med. 2008;
358(4): 369-74. doi: 10.1056/NEJMoa0707255.
- Sykes M. Mixed chimerism and transplant tolerance. Immunity. 2001;
- Coglan A. Saved by a pig’s heart. New Scientist. 2008; 200(2684): 8-9.
- Adams DD. Why the histocompatibility system exists and how
transplant surgeons can xenograft without rejection. QJM 2011;
104(9): 767-769. doi: 10.1093/qjmed/hcr051.