5 Transplant pathology&Amyloidosis.pptmdpath

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1. Transplant Rejection & Transplant Rejection &
AmyloidosisAmyloidosis
Dr R Vijayashree
Lecture 24

2. Transplant rejectionTransplant rejection
•Mechanisms of transplant rejection
•T cell mediated cellular
–Direct pathway via recipient CD4+ and CD8+
recognition of MHC Class I antigens on donor
APCs
–Indirect pathway whereby processing of
antigen by the recipient’s APCs is required
•Antibody mediated

4. Morphology of transplant Morphology of transplant
rejection rejection
•Hyperacute: due to preformed antibodies,
usually in multiparous women, those having
received an earlier transplant or multiple
transfusions - rare because of antibody
screening
•Acute: mixed antibody and T-cell response,
usually controlled adequately by chemotherapy
•Chronic: rejection occurs months to years post-
transplant

5. Hyperacute RejectionHyperacute Rejection
•Occurs within minutes
•Grossly kidney purple
and swollen, soft &
flabby
•Widespread acute
arteritis and arteriolitis
•Thrombosis of vessels,
Ischemic necrosis
•Results in loss of graft

6. Hyperacute rejectionHyperacute rejection
•Thrombi in
glomerulus and fibrin
in artery. Anti-donor
antibodies bind to
donor endothelial
cells and activate the
complement cascade
and clotting cascade.Fibrin in artery
Thrombus in
Glomerulus

7. •Occurs as early as 10-14 days. May occur months to
years later.
•Decreased renal function. May have fever and
tenderness of the graft.
Cellular or vascular
Vascular:
•Humorally mediated
•Vascular inflammation –
•Necrotizing vasculitis (rejection vasculitis); sometimes
thickening & fibrosis
•Responds less well to therapy
Acute RejectionAcute Rejection

8. •Cell mediated
•Lymphocytic infiltrate
of the interstitium
and tubulitis (T cells
of both types – CD4
& CD8)
•Increased expression
of IL2
R
•Responds well to
therapy
Acute Cellular RejectionAcute Cellular Rejection

9. Acute Vascular RejectionAcute Vascular Rejection
•Humorally mediated
•Vascular inflammation
–Intimitis
–Necrotizing vasculitis (rejection vasculitis)
•Responds less well to therapy

10. Chronic RejectionChronic Rejection
•Progressive rise in
creatinine over 4-6
months
•Vascular changes
–Intimal fibrosis
–Progressive luminal
narrowing
•Interstitial fibrosis and
tubular atrophy
•Ischemic
glomerulosclerosis
•No effective therapy

11. Methods of Increasing Graft Methods of Increasing Graft
SurvivalSurvival
•HLA matching
–Class I for live related
–Also class II for cadaver transplants
•Immunosuppression of the recipient
–Cyclosporine, Azathioprine, Steroids,
Rapamycin & mofetil
–Blocking the co-stimulators (CD 80 & CD 40)
by immunotherapy (CTLA4Ig)

12. Transplantation of Other Solid Transplantation of Other Solid
OrgansOrgans
•Liver
•Heart
–No HLA matching is usually done
•Lungs
•Pancreas
•Small intestine

13. Bone Marrow TransplantBone Marrow Transplant
•Hematopoietic malignancies
•Aplastic anemia
•Immunodeficiency states
•Certain non-hematopoietic malignancies
Complications of Bone marrow transplant
•Graft versus Host Disease
•Rejection of allogeneic marrow cells

14. Graft vs. host (GVH) reactionsGraft vs. host (GVH) reactions
•Occurs primarily in bone marrow
transplantation, because immunologically
active cells are given to generally immune
ablated host
•May also occur in immune deficient patients
given blood transfusions containing HLA-
incompatible lymphocytes
•Treated with immunosuppressive drugs such as
cyclosporine (inhibits IL-2 formation) or anti –
thymocyte globulin (anti-CD3)
•Depletion of donor T cells eliminates GVH

15. GVH diseaseGVH disease
Acute
•Within days to weeks
•Skin, liver & intestine are
affected
•Generalized rash with
desquamation, jaundice,
diarrhoea
•CMV infection – sometimes fatal
Chronic
•May follow acute or may begin
insidiously
•Changes may resemble
scleroderma

16. AmyloidAmyloid
•Amyloid is an abnormal proteinaceous
substance deposited in extra-cellular
space
•Distinguished grossly by a starch-like
staining reaction with iodine (thus the
term amyloid),

17. AmyloidAmyloid
•Microscopically by its eosinophilic,
amorphous, hyaline like appearance and
Greenish birefringence under polariser
when stained with Congo red;
•By its protein fibril structure (EM)

18. AmyloidosisAmyloidosis
•Amyloidosis is not a single disease but a
group of disease processes producing
similar deposits
•It is a misfolded protein and is deposited
as fibrils; accounts for about 90% of the
amyloid material.
•Amyloid P (pentagonal) component, a
glycoprotein forms 5%.

19. Components of Amyloid DepositsComponents of Amyloid Deposits
•Amyloid deposits typically contain three
components.
–Amyloid protein fibrils account for about 90% of the
amyloid material and comprise one of several
different types of proteins with the capacity to fold
into what are called "beta-pleated" sheet fibrils,
with binding sites for Congo red.
–Amyloid P (pentagonal) component (AP), a
glycoprotein related to normal serum amyloid P
(SAP),
–Sulfated glycosaminoglycans (GAG), complex
carbohydrates of connective tissue.

20. Chemical Nature of amyloidChemical Nature of amyloid
•15 chemically distinct forms three are most
important
•AL(light chain) derived from plasma cells and
conatains immunoglobulin light chains.
•AA(amyloid-assoc) is unique immunoglobulin
protein synthesized by the liver.
•Aβ amyloid – cerebral lesions of Alzheimer
disease.

21. Chemical Nature of amyloidChemical Nature of amyloid
•Transthyretin(TTR)- transport protein of
thyroxine & retinol- mutant form seen in
certain type.
•β2-microglobulin- MHC class I hemodialysis.
•β-amyloid protein
•Prion protein aggreagtes

22. AmyloidosisAmyloidosis
•Amyloid deposition may be either a.
–Primary (idiopathic) process without known
antecedent ( tends to involve mesodermal tissues,
most frequently affecting peripheral nerves, skin,
tongue, joints, heart, and liver) or.
–Secondary to some other condition and may be
localized to one specific site or generalized
throughout the body (systemic), usually with fatal
consequences (mainly affects parenchymatous
organs, such as spleen, kidneys, liver, and adrenals).

23. Clinical
Classification
Amyloid type Precursor
Systemic Amyloidosis
Immunocyte dyscrasia (primary) AL Ig light chain
Reactive amyloidosis (secondary) AA SAA
Hemodialysis associated Aα
2
m α-2 micro-globulin
Familial Mediterranean fever AA SAA
Familial amyloidotic polyneuropathy ATTR Trans-thyretin
Senile Systemic amyloidosis ATTR Trans-thyretin
Localised Amyloidosis
Senile cerebral (Alzheimer’s) Aβ APP
Endocrine
• Medullary carcinoma thyroid
A Cal Calcitonin
• Islet of Langerhans (DM type II) AIAPP
Islet amyloid
peptide
Isolated atrial amyloidosis AANF
Atrial natriuretic
factor

24. Immunocyte dyscrasia (primary)Immunocyte dyscrasia (primary)
•5-10% of patients who have pre-existing or
coexisting multiple myeloma.
•The AL fibrils are derived from circulating light
chains by proteolytic cleavage and conversion
to an insoluble form.
•is also associated with some other rare
monoclonal gammopathies (solitary myeloma,
Waldenstrom's macroglobulinemia, or heavy
chain disease)

25. Reactive Systemic amyloidosisReactive Systemic amyloidosis
•occurs mainly as a complication of long standing
inflammatory diseases, most frequently RA (5-10%
of patients), dermatomyositis, scleroderma,
regional enteritis, and ulcerative colitis.
•Prior to the antibiotic era, TB, chronic
osteomyelitis, and bronchiectasis,
•often develops as a complication of skin and lung
abscesses in heroin abusers.
•may occur in association with Hodgkin's disease
and renal cell carcinoma.

26. Familial amyloidosisFamilial amyloidosis
1.Familial Mediterranean fever (A. Recessive)
a)Autosomal recessive with gene product, Pyrin;
b)Fever, serosal inflammation with systemic deposition
of AA fibrils;
c)Seen in people of Sephardic Jewish, Armenian, &
Arabic descent.
2.Familial amyloid neuropathies
a)an autosomal dominant disorder occurring in different
parts of the world (Sweden, Portugal, Japan, U.S.)
b)Amyloid deposition of a mutant form of transthyretin
occurs in peripheral nerves

27. •Haemodialysis assoc amyloidosis
β
2
-microglobulin deposition
Present in high concentration in renal diseases-
cannot be filtered thro cuprophane membrane.
Deposition in synovium, joints and tendon sheaths.
•Localized amyloidosis-
Nodular tumour forming amyloid- lung, skin, tongue,
larynx, urinary bladder. Infiltration of lymphocytes,
plasma cells seen around.
•Endocrine amyloid-
medullary carciunoma of thyroid,islet tumours,
haeochromocytomas,undifferentiated carcinomas of
stomach.,Type II DM.
•Amyloid of aging-
Senile systemic amyloidosis, TTR mutant protein.

28. Stimulus Unknown Chronic Inflammation Mutation
Production of abnormal proteins
Production of normal amount
of mutant protein
Ig light
chains
SAA Protein Transthyretin
Insoluble
fibrils
AL protein
AA protein
ATTR
protein
Soluble precursor
misfolded protein
Monoclonal B-
lymphocyte proliferation
Plasma cells
Macrophage
activation
Interleukin 1 & 6
Liver cells
Limited
proteolysis
Limited
proteolysis
Pathogenesis of major forms of Amyloid

29. Some clinical and laboratory manifestations Some clinical and laboratory manifestations
of Amyloidosisof Amyloidosis
Involvement Manifestations
Kidney Proteinuria, Renal Failure, Nephrotic
syndrome
Heart Congestive failure, Cardiomegaly
GIT Macroglossia,obstruction,malabsorption
Liver, Spleen Hepatomegaly,Splenomegaly
Skin Waxy papules
Bone marrow Multiple myeloma/plasmacytosis
Serum and UrineMonoclonal Ig and light chains
Amyloid accumulates progressively and
encroaches on surrounding tissues causing
pressure atrophy.

31. Cross Section of Amyloid
Myocardium Stained With
Lugol's Iodine Solution
Amyloid Kidney
Congo red (polarized)
Amyloid Fibril - EM
“Lardaceous” spleen
Amyloidosis liver Amyloidosis kidney

32. •A 15 year old male underwent bone marrow
transplantation for acute lymphocytic leukemia. About a
month after transplantation, his pancytopenia was
resolving as the marrow showed engraftment, and there
was no evidence for recurrent leukemia. However, he
developed a fine scaling skin rash, increasing jaundice,
and diarrhea.
1.What is the name of this complication following
transplantation? What are the findings below here?
2.How does this occur?
3.In what types of transplants does this occur?