SECOND MBBS, PATHOLOGY, MEDICAL COUNCIL OF INDIA, COMPETENCY BASED UNDERGRADUATE CURRICULUM FOR THE INDIAN MEDICAL GRADUATE, 2018

1. PA9.3
DESCRIBE THE HLA SYSTEM & THE IMMUNE
PRINCIPLES INVOLVED IN TRANSPLANT &
MECHANISM OF TRANSPLANT REJECTION
Dr IRA BHARADWAJ
MCI TEACHER ID: PAT 2300569
KUHS FACULTY ID: M21512

2. TEXT BOOK REFRENCES
• ROBBINS BASIC PATHOLOGY
• HARSH MOHAN TEXTBOOK OF PATHOLOGY
• SELF ASSESSMENT & REVIEW OF PATHOLOGY BY ARVIND ARORA
• TEXTBOOK OF MICROBIOLOGY BY DR C P BAVEJA
• OTHER STANDARD REFRENCES

3. SPECIFIC LEARNING OBJECTIVES
• ROLE OF HLA / MHC IN IMMUNITY
• ROLE OF HLA A,B,D [MHC 1&2] IN IMMUNITY
• TYPES OF TRANSPLANTED GRAFTS
• ALLOGRAFTS
• TYPES OF TRANSPLANT REJECTIONS
• PATHOGENESIS OF SOLID ORGAN REJECTION
• TYPES OF SOLID ORGAN REJECTION
• GRAFT VS HOST DISEASE
• TYPES OF GVHD
• MCQs

4. HLA / MHC
Major Histocompatibility Complex
• MHC is a genetic “LOCUS” on Chromosome 6p, which codes
for cell surface compatibility i.e., they regulate expression of
cell surface antigen
• Also called HLA (Human Leukocyte Antigens) in humans and
H-2 in mice
• It’s major job is to make sure all self cell antigens are
recognized and “tolerated”, because the general rule of the
immune system is that all UN-recognized cells will NOT be
tolerated

5. MHC MOLECULES
(Gene Products)
HLA A & B [MHC 1]
• Expressed on all nucleated cells and platelets on the surface
of the cell,
• It is a glycoprotein & antigenic.
•T8 lymphocytes recognize & interact with it to
become activated & cause cytolysis
• They are involved in graft rejection

6. MHC MOLECULES
(Gene Products)
HLA D [MHC II]
• Expressed on all APC’s, i.e., Langerhans cells, macrophages,
dendritic cells & B lymphocytes on cell surface
• It is a glycoprotein & antigenic
•T4 lymphocytes interact with it and are activated
immunologically
• It is primarily responsible for graft vs host disease

7. TYPES OF GRAFTS [TRANSPLANTS]
• AUTOGRAFT ( autogenic ) – graft from self eg, skin grafting
• ISOGRAFT ( syngraft ) – graft from identical twin
• ALLOGRAFT ( homograft ) - graft from genetically unrelated
member of same species
• XENOGRAFT( heterograft ) – graft from different species

8. ALLOGRAFT
• Allograft is the most commonly performed transplant
procedure
• Main problem of this procedure is rejection of the
transplanted tissue
• Most common transplanted organ is kidney

9. TRANSPLANT REJECTION
Two main types of rejections occur
• GRAFT REJECTION BY HOST seen in solid organ transplant
e.g. kidney
• HOST REJECTION BY GRAFT known as GRAFT Vs HOST
DISEASE ( GVHS ) occurs in hematopoietic tissue transplant
e.g. bone marrow

10. REJECTION OF TRANSPLANT [SOLID ORGAN]
PATHOGENESIS
• PRESENCE OF PREFORMED ANTI DONOR ANTIBODIES
• RECOGNITION OF FOREIGN MHC MOLECULES ON GRAFT BY
HOST IMMUNE SYSTEM
DIRECT RECOGNITION via DONOR MHC
INDIRECT RECOGNITION VIA HOST APC

11. REJECTION OF SOLID ORGAN TRANSPLANT
PREFORMED ANTI DONOR ANTIBODIES
PRESENCE OF PREFORMED ANTI DONOR ANTIBODIES ARE
SEEN IN:
• Pre transfused host
• Multiparous women
• Patient with previously rejected transplant

12. REJECTION OF SOLID ORGAN TRANSPLANT
DIRECT RECOGNITION via DONOR MHC
DIRECT RECOGNITION OF FOREIGN MHC MOLECULES ON
GRAFT BY HOST IMMUNE SYSTEM
DIRECT RECOGNITION – via donor MHC 1 on all nucleated
donor cells
MHC I (HLA-A,B) on donor cells is
• Recognized directly by CD8+TL of host,
• Which are then activated to form cytotoxic T lymphocytes
[CTL],
• Causing apoptosis of donor cells

13. REJECTION OF SOLID ORGAN TRANSPLANT
DIRECT RECOGNITION via DONOR MHC
DIRECT RECOGNITION OF FOREIGN MHC MOLECULES ON
GRAFT BY HOST IMMUNE SYSTEM
DIRECT RECOGNITION – via donor MHC II on all donor antigen
presenting cells
MHC II (HLA-D) on donor APC cells - Directly activate CD4+TL
of host, leading to production of:
• Cytokines and
• Activation of BL to produce antibodies against donor cells
• This causes necrosis & inflammation of donor tissue

14. REJECTION OF SOLID ORGAN TRANSPLANT
INDIRECT RECOGNITION via HOST APC
INDIRECT RECOGNITION OF FOREIGN ANTIGENS ON GRAFT
BY HOST ANTIGEN PRESENTING CELLS
Donor antigens, which are foreign to the host are picked up
by host APC (dendritic cells, macrophages & B Lymphocytes)
• Leading to activation of host immune system
• Especially via CD4+TL, which secrete cytokines & enhance
antibody production
• Leading to necrosis & inflammation of graft tissue

15. REJECTION OF SOLID ORGAN TRANSPLANT
SUMMARY OF PATHOGENESIS

17. REJECTION OF SOLID ORGAN TRANSPLANT
ROLE OF CD 8+ T LYMPHOCYTES
CD8+TL ARE IMMUNOLOGICALLY ACTIVATED TO TRANSFORM
INTO CYTOTOXIC T LYMPHOCYTES, WHICH RESULT IN:
• Apoptosis / necrosis of donor parenchymal cells
• Apoptosis / necrosis vascular endothelium [donor tissue],
leading to
• Thrombosis & ischemia
• All above factors contribute to necrosis of graft i.e., rejection
of graft

18. REJECTION OF SOLID ORGAN TRANSPLANT
ROLE OF CD 4+ T LYMPHOCYTES
CD4+TL ARE IMMUNOLOGICALLY ACTIVATED AND
TRANSFORM INTO VARIOUS SUBSETS LIKE Th 1 & Th 17
Activated Th1 &17 subsets leads to type 4 [delayed type of]
hypersensitivity reaction, as well as activation of B
lymphocytes to produce antibodies
• DTH & PROLONGED DTH lead to inflammation & granuloma
formation
• ANTIBODIES formed against donor vascular endothelium are
most important and lead to type 2&3 hypersensitivity
reactions, which activate complement – inflammation -

19. TYPES OF SOLID ORGAN [KIDNEY] REJECTION
• HYPERACUTE
• ACUTE
• SUBACUTE
• CHRONIC

20. HYPERACUTE REJECTION
• Occurs due to preformed anti donor antibodies in recipient,
rare now due to screening of recipient Abs for donor Ags
• It is seen within minutes of vascular anastomosis
• Kidney is cyanotic, mottled & flaccid, no urine/ few drops of
hemorrhagic fluid may be excreted
• Histology – all vessels show acute fibrinoid necrosis,
precipitate of fibrin & cellular debris is seen in lumen of
blood vessels

21. ACUTE REJECTION
OCCURS WITHIN DAYS DUE TO CELLULAR & HUMORAL
REACTIONS
CELLULAR RECATIONS
CD8+TL & CD4+TL ( DTH ) reaction, leading to
• Endothelitis of glomerular & peritubular capillaries,
• Infiltration by lymphocytes,
• Edema & hemorrhage,
• Necrosis of tubular cells, causing acute renal failure [ARF]

22. ACUTE REJECTION
HUMORAL REACTION
Type 2 &3 hypersensitivity reactions due to anti donor
antibodies, leading to
• ACUTE NECROTIZING VASCULITIS – Ag-Ab complexes
deposited in wall of BV cause
• Necrosis & inflammation, followed by
• Thrombosis & consequent ischemia, which leads to
• Atrophy & necrosis of graft

23. SUB ACUTE REJECTION
More frequently due to Ag-Ab COMPLEX (type III
hypersensitivity reaction) which lead to
• Inflammation &
• Cytokines which cause proliferation of fibroblasts, myocytes
in BVs,
• Narrowing the vascular lumen, leading to ischemia, atrophy
& infarction of graft

24. D/D OF REJECTION
• Cyclosporine toxicity which shows arteriolar hyaline
deposits in renal biopsy, may also present with similar
clinical features & should be considered in D/D of acute
rejection
• Arteriosclerosis is an important D/D of sub acute rejection
& can be distinguished by renal biopsy which shows
presence of complement breakdown products, like C4d in
rejection

25. CHRONIC REJECTION
Appears much later, after many months & years
• It is due to cytokines, which cause
• Proliferation of vascular intimal smooth muscles & increased
extracellular matrix
• Narrowing of lumen of BV – decreased blood flow & slow
ischemia, resulting in
• Atrophy & fibrosis of glomeruli, tubules & interstium, leading
to chronic renal failure[CRF]

26. METHODS OF IMPROVING GRAFT SURVIVAL
• SCREENING RECIPIENT BLOOD FOR PREFORMED DONOR
ANTIBODIES
• HLA MATCHING OF RECIPIENT & DONOR (HLA controls
expression of MHC I & II )
• IMMUNOSUPPRESSIVE THERAPY – main side effects are
infections & tumors

27. GRAFT Vs HOST DISEASE
• IMMUNOCOMPETENT DONOR T LYMPHOCYTES [CD 4&8]
PERCEIVE RECIPIENT (HOST) Ags AS FORGIEN & REACT
• HOST IS IMMUNOCOMPROMISED, NO HOST REACTION TO
DONOR CELLS
[before hematopoietic transplant , host is immune depleted]

28. GRAFT Vs HOST DISEASE
ACUTE GVHD – (days to wks) – epithelial necrosis in gut, skin,
liver
CHRONIC GVHD – (late) characterized by
• Autoimmune diseases
• Immunodeficiency

29. MCQ
HLA-I present on
a)All nucleated cells b) Only on cells of immune system
c) Only on B- cells d) Only on T-cells
Grafting done between genetically different individuals of the
same species is
a)Autograft b) Allograft
c) Isograft d) Xenograft

30. MCQ
Preformed antibodies cause
a) Hyperacute rejection b) Acute rejection
c) Chronic rejection d) Acute humoral rejection
Graft rejection is
a) Cell mediated b) Humoral c) Both
d) none

31. MCQ
Cell responsible for GVHD is
a) Immunocompetent T cell donor
b) Immunocompetent T cell recipient
c) Immunocompetent B cell donor
d) Immunocompetent B cell recipient

32. MCQ
Cyclosporine toxicity, following renal transplant; presents as
a) acute renal failure
b) Chronic renal failure
c) Fibrinoid necrosis
d) Coagulative necrosis

33. MCQ
Type of necrosis seen in transplant rejection is
a) Coagulative necrosis
b) Fat necrosis
c) Fibrinoid necrosis
d) Liquefactive necrosis

34. MCQ
Chronic solid organ transplant rejection is due to
a) Antibodies
b) Cytokines
c) Chemokines
d) Antigens

35. MCQ
MHC II is present on all except
a) Langerhans cell
b) Langhans cell
c) Macrophage
d) Dendritic cell

36. MCQ
Acute renal transplant rejection presents as all, except
a) Glomerulonephritis
b) Pyelonephritis
c) Acute tubular necrosis
d) Interstitial nephritis