This document discusses transplantation immunology and tumor immunology. It defines types of transplants like autograft, isograft, allograft, and xenograft. It describes mechanisms of rejection like hyperacute, acute, and chronic rejection. It discusses antigens, immune cells, and cytokines involved in rejection. It also covers tumor antigens, mechanisms of immune response against tumors, and ways tumors evade the immune system.

1. Transplantation and tumor
Immunology
Presenter: Mohd Bakar
Facilitator: Dr. S Masoud

2. Objectives
• At the end of presentation students should be able
to
• Describe types of rejection (hyperacute, accelerated
acute, acute and chronic)
• Explain Immunological mechanisms of
transplantation rejection
• Explain ABO and other Blood types
• Understand GVHD
• Describe Immunosuppressive drugs
• Discuss tumor immunology

3. Introduction
• Immune system has evolved to discriminate
between self and non self
• Once foreignness has been established against
non self, be it a tumor cell or transplanted tissue,
then the immune response proceeds toward its
ultimate goal of destroying it. This is known as
tumor immunology or transplantation
immunology respectively
• A major mechanism by which the immune system
kills both tumor cells and the cells of transplants
is by cytotoxic T lymphocyte

4. Transplantation immunology
• Transplantation immunology - sequence of
immunoresponse that occurs after an allograft
or xenograft is removed from donor and then
transplanted into a recipient
• Therefore, the immune response of the recipient
to the donor tissue is major barrier to the success
of transplantation

5. Types of Transplant
• Autograft.
• Isograft.
• Allograft
• Xenograft

6. Types of Transplantation
• Autograft: Is self-tissue transferred from one body site
to another in the same individual
• Autograft tissue is recognized as a self/autologous and
therefore no immune response induced against it
• Isograft: is tissue transferred between genetically
identical individuals
• Example, transplantation of kidney between
homozygotic twins
• The two individuals are histocompatible and thus no
immunoresponse induced

7. Types of Transplantation cont..
• Allograft: is tissue transferred between genetically
different members of the same species
• Graft recognized as a foreign and therefore
immunologically rejected
• The donor and recipient is therefore
histoincompatible
• Xenograft: Is tissue transferred between different
species
• Donor and recipient again described as
histoincompatible

8. Xenogeneic Transplantation
• A major barrier to xenogeneic transplantation is the
presence of natural antibodies that cause
hyperacute rejection
• Donors of choice: Pigs
– Of similar size of organs and erythrocytes
Problems:
– Hyperacute rejection
1. Humans have antibodies to pig endothelial
carbohydrates
– natural antibodies vs. Gal (galactose-α-1,3-galactose)
causing hyperacute rejection

9. Xenogeneic Transplantation
2. Pig’s cells are attacked by human complements
Potential solutions:
• Transgenic pigs expressing human DAF, which
prevents complement reaction
• Transgenic pigs that don’t express the reactive
antigens
• Advantage:
• MHC molecules of different species are so different
from those of humans that human T cells can not
recognize them. So T-cell mediated rejection is mild

10. Components of the Immune system
involved in graft Rejection
1. Antigen presenting cells –
Dendritic cells
Macrophages
Activated B Cells
2. B cells and antibodies –
Natural antibodies
Preformed antibodies from prior sensitization

11. Components of the Immune system
involved in graft Rejection
3. T cells
4. Other cells –
Natural killer cells
T cells that express NK cell – associated Markers
Monocytes/Macrophages

12. Role of immune response in allograft
rejection
• Recognition of transplanted cells is determined
by polymorphic genes (MHC) inherited from both
parents and are expressed co-dominantly
• Alloantigens elicit both cell-mediated and
humoral immune responses
• Histocompatibility antigens are cell surface
expressed on all cells (class I) and on APC,
B cells, monocytes/macrophages (class II)
• They are targets for rejection

13. Role of immune response in allograft
rejection cont..
• MHCs are the primary antigens that elicit the
immune response of transplant rejection
• The chances of any two people inheriting the
same two alleles of MHC I and of the same blood
type is staggeringly low, except with close
relatives

14. Recognition of Alloantigens
Direct Presentation
 Donor tissue dendritic cells migrate to lymph nodes,
stimulating a measurable percentage of recipient T cells
The host T cells in the lymph node recognize either the
allograft HLA or an associated bound peptide.
 In this case, alloreactive T cells are stimulated by donor
APCs which express both the allogeneic MHC and
costimulatory activity
– Involves both CD8+ and CD4+ T cells.

15. Indirect Presentation
 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

16. Activation of Alloreactive T cells and
Rejection of Allografts
• Donor APCs migrate to regional lymph nodes and
are recognized by the recipient’s TH cells
• Alloreactive TH cells in the recipient induce
generation of TDTH cell and CTLs then migrate into
the graft and cause graft rejection

17. Role of CD4+ and CD8+ T Cells
• CD4+ differentiate into cytokine producing
effector cells
– Damage graft by reactions similar to DTH
• CD8+ cells activated by direct pathway kill
nucleated cells in the graft

18. Role of Cytokines in Graft Rejection
• IL – 2, IFN – , and TNF -  are important mediators of
graft rejection
• IL – α promotes T-cell proliferation and generation of T –
Lymphocytes
• IFN -  is central to the development of DTH response
• TNF -  has direct cytotoxic effect on the cells of graft
• A number of cytokines promote graft rejection by
inducing expression of class – I or class – II MHC
molecule on graft cell
– The interferon (α,  and ), TNF – α and TNF -  all
increases class – I MHC expression, and IFN - 
increases class – II MHC expression as well

19. Effector Mechanisms of Allograft
Rejection
• Hyperacute Rejection
• Acute Rejection
• Chronic Rejection

20. Hyperacute Rejection
• Characterized by thrombotic occlusion of the graft
• Begins within few minutes to a few hours after
anastomosis
• Pre-existing antibodies in the host circulation bind to
donor endothelial antigens
• Activates Complement Cascade
• Xenograft Response
• Cell mediated immunity is not involved
• At present there is no therapy for successful
termination of hyperacute rejection

21. Hyperacute Rejection cont..

22. Acute Rejection
• Vascular and parenchymal injury mediated by T
cells and antibodies that usually begin after the
first week of transplantation if there is no
immunosuppressant therapy and recipient has
not previously sensitized to transplant
• Incidence is high (30%) for the first 90 days
• May be reduced by immunosuppressive therapy
such as antilymphocytic serum

23. Acute rejection (within weeks) is caused by effector CD4+ Th1 cells
or CD8 T cells responding to HLA differences between donors and
recipients (similar to TYPE IV hypersensitivity reaction);
Can be prevented by immunosuppressive drugs or anti-T cell
antibodies
Accelerated Acute rejection (within days) is mediated by sensitized
(memory) T cells by previous grafts or exposure
Acute rejection cont..

24. Chronic Rejection
• Occurs in most solid organ transplants (Heart, Kidney,
Lung, Liver)
• Characterized by fibrosis and vascular abnormalities
with loss of graft function over a prolonged period
• Caused by both antibody and cell mediated immunity
occurs months after transplanted tissue has assumed
its normal function
• Because damage caused by immune injury has already
taken place immunosuppressive therapy at this point
is useless

25. Chronic rejection cont..
Occurs months or years after transplantation.
Thickening of blood vessel walls leading to ischemia
The mechanism is not entirely clear but it may be due to chronic
DTH response
localized tissue anemia due to obstruction of the inflow of arterial blood

26. Graft vs. Host Disease
• A condition that occur when donor bone marrow
or stem cells attack the recipient
• Caused by the reaction of grafted mature T-cells in
the marrow inoculum with alloantigens of the host
Acute GVHD
– Characterized by epithelial cell death in the skin,
GI tract, and liver
Chronic GVHD
– Characterized by atrophy/weaken and fibrosis of
one or more of these same target organs as well
as the lungs

27. Two types of alloreactions

28. Immunosuppressive Agents
Immunosuppression can be brought about by 3
different ways :-
Surgical ablation
Total Lymphoid Irradiation
Immunosuppressive drugs

29. Immunosuppressive Drugs
• Three main immunosuppressant drugs
Cyclosporines act by inhibiting T-cell activation, thus
preventing T-cells from attacking the transplanted
organ.
Azathioprines disrupt the synthesis of DNA and
RNA and cell division
Corticosteroids such as prednisolone suppress the
inflammation associated with transplant rejection

30. Immunosuppression Therapy

31. Immunosuppressive Therapy
Downsides
Must be maintained for life
Toxicity
Susceptibility to infections
Susceptibility to tumors

32. The fetus is allograft that is tolerated repeatedly
 Fetus carries paternal MHC and minor H antigens
that differ from those of mother
 Still, fetus is an allograft that is not rejected
 Women who born several children make antibodies
directed at father’s MHC proteins
 Possible explanations of this puzzle:
 Lack of classic MHC antigens on cells of trophoblast
cells (TC) (protection from maternal T cells)
 Presence of HLA-G antigens on TC (protection from
NK cells)
 Secretion of suppresive cytokines by TC and uterine
epithelium (TGF-beta, IL-10, IL-4)

33. Tumor immunology
• Tumor cell possesses antigenic component on its
surface that give rise to immunoresponse
• Those antigenic components are unique to
cancerous cells and are not present on their
normal counterparts ⇒ and are referred to
tumor-specific antigens (TSAs )
• Other tumor antigens may represent structures
that are common to both malignant and normal
cells but are masked on the normal cells and
become unmasked on malignant cells

34. Tumor immunology cont..
• Also other antigens on tumor cells represent
structures that are qualitatively not different
from those found on normal cells but that are
over expressed–present at significantly increased
numbers on the cancer cell as products of cellular
oncogenes ⇒ tumor-associated antigens (TAAs)
• High levels of a growth factor receptor due to
increased expression of the neuoncogene
products found in a number of human breast
cells, and elevated ras

35. Tumor immunology cont..
• Still other antigens on malignant cells represent
structures that are present on fetal or embryonic
cells but disappear from normal adult cells ⇒
oncofetal or oncodevelopmental antigens

36. Oncogenesis
36
proto-oncogenes
tumor
suppressor
genes
oncogenes
carcinogen
results in mutation
dysfunctional
tumor suppressor
genes
inherited
defect
increased GF
increased GF receptors
exaggerated response to GF
loss of ability to
repair damaged
cells or induce
apoptosis

37. Classification of tumor antigens
• Classified into 4 major categories
• Differ in both factors that induce malignancy and
immunochemical properties of tumor antigens

38. Antigens of tumors induced by chemical
or physical Carcinogens
• Exhibits a unique antigen specificity
• Cells of a given tumor, arising from a single
transformed cell share common antigens, but
different tumors, even if induced by the same
carcinogen, are antigenically distinct from one
another
• Therefore, no cross reactivity between such tumors
• The difference is due to random mutation induced
by carcinogen giving to large array of distinct
antigens

39. Antigens of tumors induced by chemical or
physical Carcinogens cont..
• These tumors are not expected to be amenable
to diagnosis, prophylaxis or therapy by
immunologic means
• Commonly known as Products of diverse mutated
genes
 Antigens of tumors induced by carcinogen
 Antigens of virally induced tumors
 Oncodevelopmental tumor antigens
 Antigens of spontaneous tumors

40. Antigens of virally induced tumors
• Animal studies have shown that tumors induced
by DNA or RNA oncogenic virus exhibit extensive
immunologic cross- reactivity
• This is because any particular oncogenic virus
induces expression of same antigens in a tumor,
regardless of tissue origin or animal species
• Cross-reactivity may also occur between groups
of viruses

41. Antigens of virally induced tumors cont..
• Some antigens of virally induced tumors are
encoded by the virus, but they are distinct from
virion antigens ⇒ tumor- associated antigens
(TAA)
• Occasionally, virally induced tumors may express
oncofetal antigens, encoded by the host genome

42. Oncodevelopmental tumor antigens
• Many tumors express on their surface, or secrete
into blood, products that are normally present
during embryonic and fetal development, but that
are either absent or present at very low levels in
normal adult tissue
• These structures are not immunogenic in the
autochthonous (native or original) host
• Their presence can be detected by antisera
prepared against them in allogeneic or xenogeneic
animals
• Also known as Aberrantly expressed proteins

43. Antigens of spontaneous tumors
• Spontaneous tumors are induced by natural
process due to defect in genes or as a result of
cell division
• In some cases, antigens exhibit immunologic
cross-reactivity, in other cases they do not
• Thus, antigens of spontaneous tumors seem to
resemble those of chemically or virally induced
• Also known as Products of oncogenes or mutated
tumor suppressor genes

44. Immune response to tumors
• The principal immune mechanism of tumor eradication is
killing of tumor cells by CTLs specific for tumor antigens
• This is because the tumor antigens are displayed as class
1 MHC-associated peptide
• Therefore, these antigens are recognized by class I MHC–
restricted CD8+ CTLs, whose function is to kill cells
producing the antigens
• Dendritic cells can also present ingested peptides from
tumor antigens on class II MHC molecules
• Thus, tumor antigens may be recognized by CD8+ T cells
and by CD4+ T cells

45. Immune response to tumors
Humoral mechanisms
• Lysis by antibody and complement
• Antibody-mediated and complement mediated
opsonization
• Antibody-mediated loss of tumor cell adhesion
Cellular mechanisms
• Destruction by cytotoxic cells
• Antibody-dependent, cell-mediated cytotoxicity (ADCC)
• Destruction by activated macrophages
• Destruction by natural killer (NK) cells

46. Tumors in immunosuppressed
individuals
• Tumors occur more frequently in
immunosuppressed individuals than in their
normal counterparts
• Such tumors are predominantly but not
exclusively lymphoproliferative malignancies

47. Immune surveillance
• Control and elimination of malignant cells by the
immune system is called immune surveillance
• Therefore, development of tumors in
immunocompetent individuals indicates that tumor
immunity is often incapable of preventing tumor growth
or is easily overwhelmed by rapidly growing tumors
• Furthermore, cancers have ability to evade immune
destruction
• All this prove that the immune response to tumors is
often dominated by tolerance or regulation, not by
effective immunity

48. Limitations of effectiveness of immune
response against tumors
• Tumor resides in immunologically privileged site
• Antigenic modulation of tumor antigens
• Presence of enhancing or blocking factors
• Suppressor T lymphocytes
• Immune suppression by tumor cell products

49. Evasion of Immune Responses by Tumors
• Immune responses often fail to check tumor growth
because tumors evolve to evade immune
recognition or resist immune effector mechanisms
 To be effective, immune responses must kill all the
tumor cells
– This is a greater challenge because tumors can grow
rapidly and often, the growth of the tumor simply outstrips
immune defenses
• Weak immunoresponse against tumors
– Because many tumors elicit little inflammation and co-
stimulation and may express few non-self antigens

50. Evasion of Immune Responses cont..
Some tumors stop expressing the antigens that are
the targets of immune attack
– These tumors are called antigen loss variants. The
variant tumor cells continue to grow and spread
 Other tumors stop expressing class I MHC
molecules, so they cannot display antigens to CD8+
T cells
 Tumors engage pathways that inhibit T cell activation
Express ligands for T cell inhibitory receptors such as
well as Induce only low levels of B7 costimulators on
APCs

51. Evasion of Immune Responses cont..
Still other tumors may secrete
immunosuppressive cytokines, such as
transforming growth factor β, or induce
regulatory T cells that suppress immune
responses

52. Immunodiagnosis
• May be performed to achieve two separate goals
Immunological detection of antigens specific to
tumor cells and
Assessment of host’s immune response to tumor

53. Detection of tumor cells and their
products by immunological means
• Myeloma and Bence-Jones proteins e.g. plasma
cell tumor
• AFP e.g. liver cancer
• CEA e.g. gastrointestinal cancers
• Prostate-specific antigen (PSA)
• Immunological detection of other tumor cell
markers e.g. enzymes and hormones

54. Tumor immunoprophylaxis
• Immunization against tumor itself requires that
tumor possesses specific antigens and that these
antigens cross-react immunologically with any
prepared antisera
• Efficacy of immunoprophylaxis for protection of
humans and animals against spontaneous tumors
has not been sufficiently evaluated

55. Immunotherapy of tumors
• Vaccination and adjuvant therapy
• Cytokine therapy e.g. interferon α, β, γ, IL-2, IL-4,
IL-5, IL-12, TNF, lymphokine activated killer (LAK)
cells, tumor-infiltrating lymphocytes (TILs)

56. Immunotherapy of tumors cont..
Anti-idiotype antibody therapy
• Dramatic regression have recently been reported in
several lymphoma patients
Immunotoxin therapy
• Toxins such as ricin, or radioactive isotopes attached
to tumor-specific antibodies are delivered
specifically to tumor cells for direct killing
• Extent to which these immunotoxins will prove
effective in the treatment of cancer remains to be
established