transplant immunity

1. Transplant immunity
From mythology to transgenic world….

2. Outline
• Introduction & Terminology
• History
• Types of rejection
• Immunologic Basis
• Effector mechanisms of
allograft rejection
• Laboratory work up
• Immunosuppressive therapy
• Individual transplants
• Organ donation
• Future prospects

3. Introduction
• Transplantation is one of mankind’s ancient dreams as it
is potentially curative treatment for end stage organ
failure.
• Problem? … Achieving the clinical tolerance
– in allograft/ xenograft
• Main focus is on identifying the causes and approaches
to combat rejection for better survival
– i e by recipient Immunosuppression
• Infections, Malignancy are important complications
• Shortage of organs to the current demand and ethical
issues

4. Terminology
• Donor and recipient
• Alloantigen and alloantibody
• MHC or HLA

5. Epidemiology
• Global Database on Donation and Transplantation
gathering data from 97 countries, in 2007 around
• 100,000 solid organ transplantations were performed per
year worldwide:
• 68,250 are kidney transplantations (45% from living donors),
• 19,850 are liver transplantations (14% from living donors),
• 5,179 are heart transplantations,
• 3,245 are lung transplantations, and
• 2,797 are pancreas transplantations.

6. Local statistics - ZCCK
• Hospitals - Data
reporting not
mandatory
• Mostly from mysore and
banglore
• Registered Patients
waiting
• Kidney 785
• Liver 98
• Kidney and liver 03
• Lung 8
• Kidney and pancreas 2
• Heart and lung 7
• Heart alone 19
• Donation till date
– From braindead donors
• 2007 kidney and cornea -
03
• 2008 onwards multiorgan
procured - 02
• 2009 – 11
• 2010 – 08
• 2011 – 06
• 2012 – 12
• 2013 till may – 10

7. Classification
• Based on organs transplanted
• Autograft, Isograft, Allograft, Xenograft
• Orthotopic vs heterotopic
• Fresh or stored
• Living or dead tissue

8. History

9. Cosmos and Damian:
the patron saints of transplantation
Their most famous surgical feat
occurred when they appeared in
human form and transplanted the
lower extremity of an dead
Ethiopian gladiator onto a
custodian of a Roman basilica
who had a gangrenous leg.
Altarpiece by an anonymous
painter about 1490
(Wurttenbergisches Landes
Museum in Stuttgart)

10. History
TIME LINE

11. Alexis Carrel (1873-1944)
• Alexis Carrel (Lyon, France) described
the modern method of vascular suturing
– exploited the availability of fine silk sutures from Lyon
– sewing lessons from an experienced embroideress
– end-to-end anastomosis avoiding the vascular lumen
– amongst the first to report auto-transplantation of a canine
kidney to the neck in1902
– experimented with transplantation of blood vessels, thyroid
tissue, ovary, testes, kidneys, limbs, and hearts in dogs
– experimental kidney transplantation -1912 -Nobel prize

12. Alexis Carrel
The Nobel Prize in Physiology or Medicine 1912
was awarded to Alexis Carrel "in recognition of his
work on vascular suture and the transplantation of
blood vessels and organs".
The immunological barrier

13. How is it that Rejection immune related?

14. Blood Relations
Karl Landsteiner
The Nobel Prize in Physiology or Medicine 1930 was awarded
"for his discovery of human blood groups".
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1980/speedread.html

15. Transplantation History
• P.B. Medawar (1945) skin grafts
– Self skin accepted
– Relative not accepted
REJECTION is a Immunologic phenomenon
• A. Mitchison (1950)
– Lymphocytes are responsible for rejection

17. Allograft rejection – immune related
Evidence Conclusion
Prior exposure to donor MHC
molecules leads to acclerated
graft rejection
Graft rejection shows
Memory and Specificity, two
cardinal features of adaptive
immmunity
The ability to reject rapidly
can be transferred to a naïve
individual by lymphocytes
from a sensitised individual
Graft rejection is mediated by
lymphocytes
Depletion or inactivation of T
lymphocytes by drugs or
antibodies results in reduced
graft rejection
Graft rejection can be
mediated by T-lymphocytes

18. Ancient word
chimera
with reference to an animal
composed of parts from
2 animals
(for example, a unicorn).
“natural tolerance” in freemartin cattle whose placentas fused
during their fetal development, allowing permanent mingling of
their respective blood cells and reciprocal
tolerance to allografts.

20. Raising Self-Awareness
Sir Frank Macfarlane Burnet Peter Brian Medawar
The Nobel Prize in Physiology or Medicine 1960 was awarded jointly
"for discovery of acquired immunological tolerance"
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1980/speedread.html

21. What is the MOLECULAR basis of acceptance/rejection?
In other words
reason for compatibility or incompatibility?

22. Major proteins that mediate Histoincompatibility found
• Peter Gorer (~1935)
• Gorer and Gorge Snell (~1950)
– Narrowed it down to locus causing tumour
REJECTION in inbred Mice experiments
– Same could be applied to transplant rejection
– H2 antigens are responsible for rejection
– Later identified –not one gene ..but set of closely
linked genes which are transferred vertically with
recombination as Haplotype

23. MHC - discovery
• Dausset –
• uncovered the first compatibility antigen in humans.
• He noticed that a patient receiving several transfusions of ABO
compatible blood still suffered an unexpected immune reaction.
• Dausset discovered that in this case antibodies were being launched against
white blood cells belonging to the donor only, and that these antibodies in the
patient’s serum triggered a similar reaction in half the samples of white blood
cells taken from other people.
• He called the factor responsible MAC, and this turned out to be the first of a
series of human leukocyte antigens, or HLAs.
• Now it has became clear that the HLA region constituted the
human version of the MHC, and that the HLA genes are so
variable and yet so specific for an individual that this provides a
form of fingerprint at the cellular level.

24. MHC - discovery
• Benacerraf –
• first indication that immune reactions are controlled by
genes.
• was surprised to discover that different strains of
guinea pigs launched different levels of attack towards
the same foreign antigen, and he traced the cause to
what he termed immune response genes.
• Over the years, many of these immune response
genes have been found and traced to the same
location, all being members of a previously
undiscovered cluster of genes lying within the MHC.

25. Seeking Signs of Compatibility
Baruj Benacerraf Jean Dausset George D. Snell
The Nobel Prize in Physiology or Medicine 1980
"for their discoveries concerning genetically determined structures on the
cell surface that regulate immunological reactions".

26. What is function of MHC/HLA?
As allograft rejection is iatrogenic
effect and not biological
phenomenon

27. MHC / HLA
• Immune defences must take extreme care not to avoid harming
any cells belonging to its own host.
• Achieving this requires a sophisticated self-identification system,
and this is centred on a collection of genes called the major
histocompatibility complex, or MHC, which encode proteins
known collectively as histocompatibility antigens.
• Each individual carries a unique combination of these antigens
on the surface of their cells, providing a form of biological ID
system for distinguishing one individual from another.

28. MHC / HLA
• The MHC-system provides an extraordinarily sensitive
surveillance system to detect cells with changed
membranes.
• It also provides a mechanism to kill cells that are becoming
alienated from their community in one way or another.
• The rejection of foreign grafts is then merely an unavoidable
by product.

29. Double-Checking Cells
Unmasked the true purpose of these self-recognition protein
molecules,
the major histocompatibility antigens
Peter C. Doherty M. Zinkernagel
The Nobel Prize in Physiology or Medicine 1996 was awarded
jointly
"for their discoveries concerning the specificity of the cell mediated
immune defence"

31. Successful transplant in
identical twins

32. Joseph E. Murray E. Donnall Thomas
The Nobel Prize in Physiology or Medicine 1990 was awarded jointly to
Joseph E. Murray and E. Donnall Thomas "for their discoveries
concerning organ and cell transplantation in the treatment of human
disease“
1954 Succesful kidney transplant between identical twins in Boston –
Peter Bent Brigham Hospital

33. Eichwald – Silmser effect
• Highly inbred strain of animals
– Female to male transplant  successful
– Male to female transplant rejected
As XY cells would have antigens expressed by Y
chromosome

34. Successful transplant in
unrelated donor & recipient

35. Immunosuppressants
• Corticosteroids
– Goodwin and Mims 1963 reported that they had used
corticosteroids to reverse acute rejection in a living-donor kidney
transplant recipient. Starzl and Marchioro, in 1963, confirmed the
efficacy with corticosteroids and the “almost miracle” effect.
• Azathioprine / Imuran
– Dr Dameshake and Dr Schwartz hypothesis if antimetabolites could be used for
treating leukemia – same could be used for immunosuppression – transplant
– Dr Calne used successfully in dog kidney transplants
http://cjasn.asnjournals.org/content/1/5/907.full

36. Organ and bone marrow cell transplantation developed independently
Beginning in 1962, pretransplant irradiation was replaced by daily
post-transplant drug immunosuppression for the treatment of organ recipients,
a switch in which Dr. Starzl played the dominant role.
http://www.starzl.pitt.edu/transplantation/immunology/marrow_kidney.html

37. Privileged sites
• Cornea - avascular
• Cartilage

38. Natural Allograft
• Fetus from Paternal antigens
– Protection from attack through
• Physical barrier, hCG- nonspecific immune
suppression, antigen masking by neg charged
muco polysaccharide,
• downregulation of classical MHC class I antigen
expression on trophoblast cells, which form the
external epithelial layer of the placenta,
• and maintenance of an immunologically favorable
immunosuppressive environment in the uterus.

39. Tumour as allograft

40. Xeno transplantation
http://www.stanford.edu/dept/HPS/Xenotransplants/xenotransplantation.html

44. Allograft rejection
Immunologic basis

45. Immunologic basis
• MHC / HLA role
• What Immune cells are involved?
• Immune response against alloantigens
– Direct and indirect antigen presentation

46. Immune cells involved
• The roles of the different components of the immune
system involved in the tolerance or rejection of grafts
and in graft-versus-host disease have been clarified.
• These components include:
• antibodies,
• antigen presenting cells,
• helper and cytotoxic T cell subsets,
• And
– immune cell surface molecules, MHC - TCR
– signaling mechanisms and
– cytokines that they release.

47. MHC / HLA
Location and organization of the
HLA complex on chromosome 6
BF, Complement factor B;
C2, complement component 2;
C4A, complement component 4A;
C4B, complement component 4B;
TAP1, transporter of antigenic peptides 1;
TAP2, transporter of antigenic peptides 2;
LTA, lymphotoxin A;
LTB, lymphotoxin B. From Klein J, Sato A. The HLA system: first of two parts.
N Engl J Med 2000;343:703

48. Structures of HLA class I and class II molecules.
β2-Microglobulin (β2m) is the light chain of the class I molecule.
TM, Transmembrane component.
From Klein J, Sato A. The HLA system: first of two parts. N Engl J Med 2000;343:704.

49. Major histocompatibility antigens
• Cell fingerprint UNIQUE for an individual
• MHC loci are highly polymorphic
• The loci are closely linked to each other, a set of alleles
is called a HAPLOTYPE
• So one inherites a haplotype from mother and another
from father
• The alleles are codominantly expressed

50. HLA Polymorphism
• HLA – A 350 alleles
• HLA – B 620 alleles
• HLA – DR 400 alleles
• HLA – DQ 90 alleles
• RESULT?
– No two individuals in an outbred population have
exactly the same set of MHC genes and molecules

51. Induction of Immune Responses
Against Transplants
• alloantigens and xenoantigens:
– graft derived antigens that serve as the targets of
rejection
• the antibodies and T cells that react against these
antigens are said to be alloreactive and xenoreactive,
respectively.
• allorecognition
– direct
– indirect

52. The Immunology of Allogeneic
Transplantation
• Recognition of transplanted cells that are self or foreign
is determined by polymorphic genes (MHC) that are
inherited from both parents and are expressed co-dominantly.
• Alloantigens elicit both cell-mediated and humoral
immune responses.

53. Recognition of Alloantigens
• Direct Presentation
– Host T cell (TCR) directly
recognises allogenic antigen on
donor cells with presented along
with donor MHC, class I OR II
– This is violation of MHC restriction
• That is in every individual, all
the T cells are educated to
recognise foreign antigens
displayed by only that
individual’s MHC molecules.
• It is immunologic cross
reaction
– Allogenic cells evoke strong T-CELL
response
• These are new that not
thymus educated
• High number of MHC
molecules presenting
antigens
• Costimulation
MHC I – CD8  ENDOTHELITIS
MHC II – CD4 IFN G  ACTIVATED MACROPHAGE

54. • Indirect Presentation
• The physiologic route
Donor MHC is processed and presented by recipient APC
Basically, donor MHC molecule is handled like any other
foreign antigen
• Involve only CD4+ T cells.
• Antigen presentation by class II MHC molecules

55. Role of Cytokines in Graft Rejection
IL – 2, IFN – g, and TNF - b
…are important mediators of graft rejection.
• IL – 2 promotes T-cell proliferation and generation
of T – Lymphocytes.
• IFN - g is central to the development of DTH
response.
• TNF - b has direct cytotoxic effect on the cells of
graft.

56. Role of Cytokines in Graft Rejection
• A number of cytokines promote graft rejection by
inducing expression of class – I or class – II
MHC molecule on graft cell.
• The interferon (α, b and g), TNF – α and TNF - b
all increases class – I MHC expression, and IFN
- g increases class – II MHC expression as well.

57. Effector Mechanisms of Allograft
Rejection • T cell mediated
– CTL’s kill graft cells
parenchymal,
endothelial celldeath
• Thrombosis ischemia
– helper T cell’s IFN g
 DTH reaction
• Increased vascular
permeability, local
accumulation of
lymphocytes and
macrophages
• Activated macrophage
injures graftcell,
vasculature  ishemia
• Antibody mediated
rejection
– Alloantibody + graft
endothelium+
complement injury,
2ndary thrombosis
• Adding fuel to the fire
are platelet
aggregation,
coagulation
• C4d deposit
histopathological
diagnosis
– Hyperacute rejection

58. Clinical presentation
Hyperacute Rejection
Acute Rejection
Chronic Rejection

60. Hyperacute Rejection
• White graft response
• Graft remains pale and is rejected within hours, without even an
attempt at vascularisation
• Characterized by
• thrombotic occlusion of the graft, Begins within minutes or hours
after anastamosis,
• Pre-existing antibodies in the host circulation bind to donor
endothelial antigens,
• Activates Complement Cascade
• Seen in Xenografts, ABO incompatibility or prior blood
transfusions or pregnancies ..sensitisation
• Avoided by blood typing and cross matching ie for Ab’s
against the cells of potential donor

61. Hyperacute Rejection
1. Preformed Ab, 2. complement activation,
3. neutrophil margination, 4. inflammation,
5. Thrombosis formation

62. Acute Rejection
• Vascular and parenchymal injury mediated mainly by CTL
cells and antibodies
• usually begin after the first week of transplantation if there is
no immunosuppressant therapy
• Incidence is high (30%) for the first 90 days

63. Acute Rejection
• T-cell, macrophage and Ab mediated,
• myocyte and endothelial damage,
• Inflammation

64. Chronic Rejection
• Indolent form occurs over mths to years
• Emerged as Important cause of graft loss compared to
acute cause which has definite treatment
• Occurs in most solid organ transplants
» Heart, Kidney, Lung, Liver
• Characterized by fibrosis and vascular abnormalities with
progressive loss of graft function over a prolonged
period.
• Arteriosclerosis – gradual narrowing of vessels
• Mediated by Tcell cytokines

65. Chronic Rejection
• Macrophage – T cell mediated
• Concentric medial hyperplasia
• Chronic DTH reaction

66. Transplantation of hematopoietic cells
• Rejection by host T cells resistant to
radiotherapy/chemothearapy
• Two problems comlplicate this form of transplant – GVH
& immunodeficiency
• Immunodeficiency due to slow reconstitution of host
immune system & inability to fully generate all necessary
immune cells  susceptible to infections mostly viral as
CMV, EBV.

67. Graft vs. Host Disease
• In bone marrow transplantation and lymphoid rich organs like liver
– Caused by the reaction of grafted mature T-cells in the marrow
inoculum with alloantigens of the host and recognise host as
foreign
– Activation of CD4 & CD8 cells  DTH & CTL responces
– Due to Mismatch between minor HLA
• Acute GVHD Days-weeks
– Characterized by epithelial cell death in the skin, GI tract, and
liver
– Bloody diarrhea, jaundice, rash
• Chronic GVHD may follow acute syndrome or occur insidiously
– Mimick autoimmune disorders like SLE
– Characterized by atrophy and fibrosis of one or more of these
same target organs as well as the lungs

68. Graft vs. Host Disease
• Lethal complication
• combination of methotrexate, corticosteroids and a calcineurin
inhibitor daily for 6 months.
– When GVHD becomes established, it is extremely difficult to
treat. Anti-thymocyte serum, steroids, cyclosporine, tacrolimus,
anti–IL-2R α chain antibodies, anti-TNF α inhibitors,
mycophenolate mofetil, and murine monoclonal antibodies to
human T-cell surface antigens
• Prevention strategy
– Minimised by HLA matching but not eliminated
– Donor T cell depletion before transplant
– Mixed blessing
• Risk of GVHD reduced but incidence of graft failure and
recurrence of leukemia increase

69. Acute GVH

70. Laboratory

71. Factors favoring allograft survival
..Rejection Prevention
• Since difference in blood group and major
histocompatibility antigens are responsible for the most
intense graft rejection reactions.
– Blood grouping:
– HLA typing
– Tissue matching

72. HLA TISSUE typing of potential donors and a
recipient
• Microcytotoxicity test for HLA antigens –
– white blood cells from the potential donors and recipient are distributed
into a series of wells on a microtiter plate,
– MULTIPAROUS WOMEN/ MONOCLONAL antibodies specific for
various class I and class II MHC alleles are added to different wells.
– After incubation, complement is added to the wells, and cytotoxicity is
assessed by the uptake or exclusion of various dyes (e.g., trypan blue
or eosin Y) by the cells.
– If the white blood cells express the MHC allele for which a particular
monoclonal antibody is specific, then the cells will be lysed upon
addition of complement, and these dead cells will take up a dye such as
trypan blue. – INVERTED MICROSCOPE
– indicate the presence or absence of various MHC alleles. It is not
possible to get 100% compatible individuals.

74. Tissue matching:
• Tissue matching was tested with the help of
– Mixed Lymphocyte Reactions (MLR) is an invitro
system for assaying TH cell proliferation in a cell
mediated response
– Cell Mediated Lympholysis (CML) is an invitro assay
of effector cytotoxic function.

75. Mixed Lymphocyte Reactions/culture
• A one-way mixed-lymphocyte reaction (MLR) can be used to
quantify the degree of class II MHC compatibility between potential
donors and a recipient.
• Lymphocytes from a potential donor that have been x-irradiated or
treated with mitomycin C serve as the stimulator cells, and
lymphocytes from the recipient serve as responder cells.
• Proliferation of the recipient T cells, which indicates T-cell activation,
is measured by the uptake of [3H]thymidine into cell DNA. The
greater the class II MHC differences between the donor and
recipient cells, the more [3H]thymidine uptake will be observed in an
MLR assay.

76. Mixed Lymphocyte Reactions/culture
contd..
• Intense proliferation of the recipient lymphocytes indicates a poor
prognosis for graft survival.
• The advantage of the MLR over microcytotoxicity typing is that it
gives a better indication of the degree of TH-cell activation
generated in response to the class II MHC antigens of the potential
graft.
• The disadvantage of the MLR is that it takes several days to run the
assay.
• If the potential donor is a cadaver, for example, it is not possible to
wait for the results of the MLR, because the organ must be used
soon after removal from the cadaver. In that case, the
microcytotoxicity test, which can be performed within a few hours,
must be relied on.

78. cell-mediated lympholysis (CML) assay
• contributed to understanding of the mechanism of target-cell killing
by CTLs.
• In this assay, suitable target cells are labeled intracellularly with
chromium-51 (51Cr) by incubating the target cells with Na51CrO.
2
4– After the 51Cr diffuses into a cell, it binds to cytoplasmic proteins, reducing
passive diffusion of the label out of the cell.
– When specifically activated CTLs are incubated for 1–4 h with such labeled
target cells, the cells lyse and the 51Cr is released.
– The amount of 51Cr released correlates directly with the number of target cells
lysed by the CTLs.
• By means of this assay, the specificity of CTLs for allogeneic cells,
tumor cells, virus-infected cells, and chemically modified cells has
been demonstrated.

80. NEWER ASSAYS
• Molecular HLA typing for alleles PCR
using sequence specific primers
– Low resolution
– Intermediate
– High
• RFLP with southern blotting

81. Various types of transplants

82. Tissue and Organ Transplantation
• Today it is possible to transplant many different
organs and tissues including.
Most common transplantation is blood
transfusion.
Bone Marrow transplantation
Organs : Heart, kidneys, pancrease, lungs,
liver and intestines.
Tissues : include bones, corneas, skin, heart
values, veins, cartilage and other connective
tissues.

83. Most Common Transplantation
-Blood Transfusion-
Transfuse Not transfused

84. Bone Marrow Transplantation
• Used for Leukemia, Anemia and immunodeficiency, especially
severe combined immunodeficiency (SCID).
• About 109 cells per kilogram of host body weight, is injected
intravenously into the recipients.
• Recipient of a bone marrow transplant is immunologically
suppressed before grafting.
– Eg. Leukemia patients are often treated with cyclo-phosphamide
and total body irradiation to kill all
cancerous cells.
• Because the donor bone marrow contains immunocompetent cells,
the graft may reject the host, causing graft versus host disease
(GVHD).

85. Stem cell transplant indications

86. Heart Transplantation :
– First heart transplant in South Africa by Dr. Christian Barnard in
1964.
– One year survival rate is >80%.
– HLA matching is desirable but not often possible, because of the
limited supply of heart and the urgency of the procedure.
Lung Transplantation :
– First attempt in 1963 by Hardy and Co - workers.
– First successful transplantation by Toronto group in 1983.
– In conjunction with heart transplantation, to treat diseases such
as cystic fibrosis and emphysema or acute damage to lungs.
– First year survival rate is about 60%.

87. Kidney Transplantation :
– Diseases like diabetes and various type of nephritis
can be elleviated by kidney transplantation.
– Survival rate after one year transplantation is >90%.
– 25,000 candidates are waiting for kidney
transplantation.
Liver transplantation :
– It treat congenital defects and damage from viral
(hepatitis) or chemical agents. (Chronic alcoholism).
– Liver one year survival exceeds 75% and five year is
70%.

88. Pancreas Transplantation :
• Offers a cure for diabetes mellitus.
• Graft survival is 72% at one year.
• Further improved if a kidney is transplanted
simultaneously.
• Overall goal - to prevent the typical diabetic secondary
complications.
Skin grafting :
• It is used to treat burn victims.
• In severe burn, grafts of foreign skin may be used and
rejection must be prevented by the use of
immunosuppressive therapy.

89. Management of rejection

91. Principles of immunosuppression
• Same for all types of organs, intensive for (vital)thoracic
organs than for kidney
• Aim is to maximise graft protection and minimise side
effects
• Most regimens are based on calcineurin blockade and
include steroid and an anti proliferative agent
• Need for immunosuppression is highest in the 1st three
months but indefinite treatment is needed
• Risk of infection and malignancy

92. Immunosuppressive Therapy
Radiation
Pharmacologic compounds
Biological agents

93. Immunosuppressants
• Resting T cell
• Early activation
• Late activation
• Proliferation
Depleting antibodies
ATG, Anti CD3, Alemtuzumab
Calcineurorin blockers
Ciclosporin, Tacrolimus
Anti CD-25
mTOR inhibitors
sirolimus, everolimus
Antiproliferatives
MMF, Azathioprine

94. Immunosuppressive Therapy
Monoclonal antibodies
• To suppress the activity of subpopulation of T-cells.
• To block co-stimulatory signals.
• Ab to the CD3 molecule of TCR (T cell receptor) complex results in
a rapid depletion of mature T-cells from the circulation.
• Ab specific for the high-affinity IL-2 receptor is expressed only on
activated T-cell, blocks proliferation of T-cells activated in response
to the alloantigens of the graft.
• To treat donor’s bone marrow before it is transplanted.
• Molecules present on particular T-cells subpopulation may also be
targeted for immunosuppressive therapy.
• Antibody to CD4 shown to prolong graft survival.
• Ab specific for implicated cytokine can prolong the survival of graft.

95. Immunosuppressive Regimen
• Induction and Maintainance
• Induction
– Ciclosporin/tacrolimus in combination with anti-CD25
monoclonal antibody
• Maintainance
– Dual therapy
» Ciclosporin/tacrolimus in combination with steroids
– Triple therapy
» Ciclosporin/tacrolimus in combination with MMF &
steroids
– Quadruple therapy
» Polyclonal antibody followed by Ciclosporin /
tacrolimus in combination with MMF & steroids

96. Complications - immunosuppression
1. Infections –
• more difficult to recognize infection in transplant recipients
• emergence of new clinical syndromes (e.g., polyomavirus type BK
nephropathy) and by infections due to organisms with antimicrobial
resistance.
• The spectrum of potential pathogens is broad, and infection often
progresses rapidly.
• Early and specific microbiologic diagnosis is essential for guiding
treatment and minimizing nonessential drug therapy. Invasive
diagnostic procedures are often required for accurate and timely
diagnosis..
• Vaccines for community acquired infections

97. • Epidemiologic Exposures
1. donor-derived infections, Example MTB, Trypanosoma
cruzi, CMV, VRE
2. recipient-derived infections, example MTB, strongyloides,
T. cruzi, CMV, EBV, HSV, VZV, HIV, HBV, HCV,
histoplasma, coccidiodes immitis, paracoccidiodes
3. nosocomial infections, methicillin-resistant Staphylococcus
aureus, vancomycin-resistant enterococcus, fluconazole-resistant
candida species, Clostridium difficile, and
antimicrobial-resistant gram-negative bacteria or
aspergillus species.
4. community infections: relatively benign in normal person,
such as aspergillus or nocardia species, C. neoformans in
birds, and respiratory viruses with subsequent bacterial or
fungal superinfection.

98. Infections:
risk
assessment

99. Donor tested positive
• Absolute contraindications
– HIV, sepsis, or unexplained fever, rash, encephalitis, or
untreated infectious syndromes.
• Contraindicated earlier but now accepted
– some livers from donors who were seropositive for Chagas’
disease have been used successfully with benznidazole
prophylaxis
– organs from donors infected with the hepatitis B virus (HBV) and
who had test results that were positive for antibodies against
hepatitis B core antigen and negative for antibodies against
hepatitis B surface antigen were rejected in the past, they are
currently used for some recipients who have been vaccinated or
who were previously infected, provided there is treatment with
specific antiserum and anti-HBV antiviral agents.

100. Factors contributing to the degree of immunologic
impairment and standard assays that assess the patient’s
risk of infection

102. • CMV
– Severe disease - FATAL
• Either endogenous / from new organ
• Match if both seronegative but not when donor
seropositive and recipient seronegative
• Clinical picture depends on organ most affected
» Pneumonia
» Gastrintestinal
» Hepatitis
» Encephalitis

103. Organ donation

104. Networks coordinating

105. Local network

107. Donor Eligibility
• Age limit between 2 yrs to 65 yrs
• Blood group same rules apply except for
Rh – not considered

108. What are the steps of donation after death?
• Once patient is admitted; all efforts are made to stabilize the patients. If all
efforts fail, patient is pronounced brain-dead after evaluation, testing and
documentation.
• Consent from the family is obtained to proceed with donation and organ
procurement organization (OPO) is informed. Consent from coroner/legal
authorities is obtained.
• In the mean time the organ donor is maintained on ventilator, stabilized with
fluids, medications and undergoes numerous laboratory tests. Recipients
are also identified for placement of organs.
• Surgical team are mobilized and coordinated to arrive at hospital removal of
organs and tissues. Donor is brought to the operating room. Multiple organ
recovery is performed with organs being preserved through special solutions
and cold packing. Ventilator support is discontinued. Donor’s body is
surgically closed and released.

109. Organ donation
• The only organisation in Karnataka through whom organ donations
and transplants are co-ordinated is ZCCK (Zonal Coordination
Committee of Karnataka For Organ Transplantation).
• ZCCK is a non-profit medical service working with centres
recognised by the government for cadaveric transplantation and co-ordination
for the same.
• A list of patients awaiting transplant is maintained. On receiving
information about potential donors, ZCCK will assess suitability for
organ donation.
• Based on the blood group and other criteria for the organ matching,
the recipients will be selected, brought into hospital and prepared for
the operation. A team of surgeons will perform the organ retrieval
from the donor. In medico-legal cases, ZCCK will help the family
with the formalities involved.

110. Future prospects

111. Transplant vaccine
• To induce donor-specific tolerance
• The use of tolerogenic dendritic cells(DC) has shown
great potential, as preliminary experiments in rodents
have demonstrated that administration of tolerogenic DC
prolongs graft survival.
• Recipient DC, Donor DC, or Donor Ag-pulsed recipient
DC have been used in preclinical studies and
administration of these cells with suboptimal
immunosuppression increases their tolerogenic potential.

112. Summary
• More than 50,000 people, waiting for compatible donor.
For ethical an practical reasons, species closely related to
human such as Chimpanzee have not been widely used.
• Xenogeneic transplantation may be major issue of
research xenograft technology including genetically
modified animal may become a new source of organ
supply.
• Techniques such as transgenic animal production and
wide range of research in this field hope to result in
opening a new window for the process of transplantation
immunology.

113. Summary
• Advances in transplantation immunology have allowed the
exponential growth of organ and tissue transplantation in medicine
over the last three decades.
• Newer immunosuppressive agents have allowed the control of solid
organ and tissue rejection and of graft-versus-host disease even
when HLA incompatibility is present.
• For the treatment of hematological disorders, including primary
immunodeficiencies, hematopoietic stem cell transplantation is not
only feasible but it is the treatment of choice in many cases.
• Future developments
– novel immunosuppressors with less toxicity and more specificity to control graft
rejection while sparing overall immunity and thereby enabling better infection
control.
– Gene therapy replacing bonemarroow/stem cell therapy

114. References
• Robins Basic pathology 8th edition
• Ananthanarayan and Paniker’s text book
of Microbiology
• Baily and Love Text book of Surgery
• Stites - Medical immunology 10th edition
• Journal articles

115. THANK YOU