1. There are several types of organ transplants including allografts between individuals, isografts between identical twins, autografts within an individual, and xenografts between species. HLA antigens are the major cause of graft rejection and play a role in antigen recognition. 2. HLA molecules present antigen peptides to T cells and are highly polymorphic. HLA Class I molecules present antigens to CD8+ T cells and Class II present antigens to CD4+ T cells. Co-stimulatory molecules also provide a second signal for full T cell activation during transplantation. 3. Acute rejection occurs early after transplantation and is mediated by T cells, while chronic rejection develops later and involves both T

1. Dr.GEOLIN MITHUN M S.,
Assistant professor
Department of general surgery
PRINCIPLES OF IMMUNOTHERAPY

2. Types of Graft
• Allograft: an organ or tissue transplanted from one individua
to another
• Isograft: organs transplanted between identical twins and a
immunologically indistinguishable
• Autograft: organ or tissue transplanted within same individu
eg, skin graft,
bone graft, Free flap
• Xenograft: a graft performed between different species
• Ortho topic graft: a graft placed in its normal anatomical site
• Heterotopic graft: a graft placed in a site different from that
where the organ is normally located

3. HLA matching
• HLA antigens are the most common cause of graft
rejection.
• Their physiological function is to act as Antigen
Recognition units*
• HLA – A, B ( Class I MHC molecules) and DR ( Class II
MHC molecules) are most important before transplant

4. Histocompatibility proteins
• The B cell receptor or antibody can identify its epitope directly without
preparation of the antigen, either on an invading pathogen itself or as a
freefloating molecule in the extracellular fluid.
• T cells, however, recognize only their specific epitope after it has been
processed and bound to a set of proteins, unique to the individual, which
are responsible for presentation of the antigen. This set of proteins,
crucial to Antigen presentation, are termed histocompatibility proteins
and, as their name suggests, were defined through studies examining
tissue transplantation

5. HLA molecules
• Are the most common cause of graft rejection
• Their physiological function is to act as antigen
recognition units
• Are highly polymorphic (amino acid sequence
differs widely between individuals)
• HLA-A, -B, -C (class I), and -DR, -DP and -DQ
(class II) are most important in organ
transplantation

6. HLA Class 1 and 2 molecules- Chromosome
6

7. MHC introduction
• MHC molecules play a role in both the innate and acquired immune
systems.
• Their predominant role, however, lies in antigen presentation within the
acquired response.
• As mentioned earlier, the TCR does not recognize its specific antigen
directly; rather, it binds to the processed antigen that is bound to cell surface
proteins
• It is the MHC molecule that binds the peptide antigen and interacts with the
TCR, a process called antigen presentation.
• Thus, all T cells are restricted to an MHC for their response. There are two
classes of MHC molecules, class I and class II.
• In general, CD8+ T cells bind to antigen within class I MHC, and CD4+ T
cells bind to antigen within class II MHC

8. HLA 1
• The α chain has three
domains, α1, α2, and
α3.
• The critical structural
feature of class I
molecules is the
presence of a groove
formed by two α helices
mounted on a β pleated
sheet in the α1 and α2

9. HLA 2
• The class II
molecules are
products of the, HLA-
DP, HLA-DQ, and
HLA-DR genes.
• The structural
features of class II
molecules are
strikingly similar to
those of
class I molecules

10. Co stimulatory molecules
• T cells recognize HLA molecules via their T-cell
receptor, but full T-cell activation also requires the
delivery of an additional or second signal by the
interaction of co-stimulatory molecules on
the surface of the antigen-presenting cell and T cell.

11. T-cell activation requires the delivery of two distinct signals to the T cell.
1. The first signal is delivered by ligation of the TCR/CD3 complex with the human leukocyte antigen
(HLA)/peptidecomplex.
2. The second signal is delivered after the interaction between pairs of co-stimulatory molecules such as CD28
with CD80/86 and CD154 with CD40

12. HLA matching not needed
• HLA matching is not needed for Liver
transplant**
• HLA matching is beneficial in Heart
transplant* but it is not practicable
because of the short cold ischemic time (3
hours) by when we could not do HLA
mismatch.

13. Rejection and
immunosuppressant
s

14. Hyperacute rejection
• Occurs within minutes to days
• Mediated by preformed antibody*
• Prior exposure to antigens
pretransplant
• Prior transplantation, Transfusion or
Pregnancy
• Immediate graft thrombosis occurs
• HPE shows Platelet and thrombin
thrombi.
• Largely preventable by Crossmatch
assay

15. Acute rejection
• Can be effectively reversed with immunosuppression.
• Occurs within first few weeks to months (m/c within first 6
months)
• Mediated by T cells*
• Massive infiltration of T cells and monocytes into allograft, leading
to destruction of the organ through direct cytolysis and generalized
parenchymal dysfunction and endothelial injury resulting in
thrombosis.
• Mostly asymptomatic, but when its symptomatic secondary to
organ dysfunction it is quite irreversible.
• Biopsy – lymphocytic infiltration, antibody deposition and
parenchymal necrosis

16. C4d Complement deposition
• The mononuclear cell infiltrate is heterogeneous and
includes cytotoxic T cells, B cells,
natural killer (NK) cells and activated macrophages.
• Antibody-mediated damage may also be present, as
evidenced by the deposition of the complement component
C4d within the graft microvasculature

17. Chronic Rejection
• Occurs after 6 months
• MC cause of Graft failure
• Most common cause of long term allograft loss.
• Indolent fibrotic process secondary to both T and B cell
process and also non-immune process
• Chronic inflammatory insults evoke a process of
epithelial to mesenchymal differentiation, leading to
epithelial cells that regress into fibrocytes

18. Chronic Rejection manifestations
• kidney: Glomerular sclerosis and tubular
atrophy;
• Pancreas: Acinar loss and islet destruction;
• Heart: Accelerated coronary artery disease
(cardiac allograft vasculopathy);
• Liver: Vanishing bile duct syndrome;
• Lungs: Obliterative bronchiolitis.

19. Risk factors of Chronic Kidney rejection**
• Previous episodes of acute rejection;
• Poor HLA match;
• Long cold ischemia time
• Cytomegalovirus (CMV) infection;
• Raised blood lipids*
• Inadequate immune suppression (including poor
compliance)
• The single most important risk factor for chronic rejection
after kidney transplantation is acute rejection (with vascular
inflammation) and recurrent
episodes of acute rejection.

20. GVHD
• Some donor organs (particularly liver and small bowel)
contain large
numbers of lymphocytes, and these may react against HLAs
expressed by recipient tissues, leading to graft-versus-host
disease (GVHD).
• GVHD frequently involves the skin, causing a characteristic
rash on the palms and soles.
• It may also involve the liver (after small bowel transplantation)
and the gastrointestinal tract (after liver transplant

21. HLA Matching
• HLA matching has a relatively small but definite beneficial effect on renal
allograft survival
(HLA-DR > HLA-B > HLAA).
• Recipients who receive well-matched renal allografts may require less
intensive immunosuppression and are also troubled less by rejection episodes
• It is common practice to express the degree of HLA matching between the
donor and recipient in terms of whether or not there are mismatches at each
locus for HLA-A, -B and -DR.
• A ‘000 mismatch’ is a ‘full-house’ or complete match, whereas a ‘012
mismatch’ is matched at HLA-A loci, has one mismatched HLA-B antigen and
is mismatched for both -DR antigens.

22. Immunosuppressants

24. THANK YOU