1. Transplant Rejection

2. Transplantation of Solid Organs :
Mechanisms Involved in Rejection :
 The antigens responsible for rejection
in humans are those coded by genes of
HLA ( Human Leukocyte Antigen ) system
[ also known as MHC ( Major Histocompatibility
Complex ) ] which are present on short arm
of chromosome 6 .
 HLA genes are highly polymorphic.

3.  Any two individuals (other than identical
twins) will express some HLA proteins that
are different (allogeneic) .
 Thus, the recipient recognize them as foreign
and attack them.
 Rejection is a complex process in which both
cell-mediated immunity and circulating
antibodies ( Humoral immunity ) play a role.

4. T Cell-Mediated Reactions:
called cellular rejection, induced by two pathways :
Direct pathway:
 Mediated by CD8+ T cells (Cytotoxic T Lymphocyte -CTL ).
 Recipient CD8+ T cells recognize antigens of graft donor
presented by donor antigen-presenting cells found in
the graft.
 CD8+ T cells recognize class I MHC antigens.
 CD8+ T cells, then differentiated into mature CD8+ T cells
dependent on release of cytokines such as IL-2
from CD4+T helper cells.
 Once mature CD8+ T cells are generated, they kill
grafted tissue by mechanisms already discussed.

5. Indirect pathway :
 Mediated by CD4+ T lymphocytes( Helper T cell) .
 Recipient CD4+ T lymphocytes recognize antigens of
graft donor after they are presented by recipient's own
antigen-presenting cells .
 CD4+ T cells recognize class II MHC antigens ,and
the result is delayed hypersensitivity type of reaction.
 It is postulated that direct pathway is major pathway
in acute cellular rejection, while indirect pathway in
chronic rejection. However, this separation is not
absolute.

6. Antibody-Mediated Reactions:
called humoral rejection, and take two forms:
Hyperacute rejection :
 occurs when preformed antidonor antibodies are
present in circulation of recipient.
 rejection occurs immediately after transplantation
 the circulating antibodies deposit rapidly on vascular
endothelium of grafted organ.
 Complement fixation occurs resulting in thrombosis
of vessels in graft, and ischemic death of graft.

7. Acute humoral rejection:
 In recipients not previously sensitized to
transplantation antigens, exposure to class I and
class II HLA antigens of donor may evoke antibodies.
 The antibodies formed, cause injury by several
mechanisms, including complement-dependent
cytotoxicity, inflammation, and antibody-dependent
cell-mediated cytotoxicity.
 The initial target of these antibodies is graft
vasculature. Thus sometimes referred to rejection
vasculitis.

8. Morphology of Rejection Reactions :
Rejection reactions are classified as hyperacute, acute, and
chronic.
Hyperacute Rejection:
 occurs within minutes or hours after transplantation.
 hyperacutely rejecting kidney rapidly becomes
cyanotic, mottled, and flaccid and may excrete few
drops of bloody urine.
 There is a rapid accumulation of neutrophils within
arterioles, glomeruli, and peritubular capillaries.
 Subsequently, these changes become diffuse and
intense, the glomeruli undergo thrombotic occlusion of
capillaries, and fibrinoid necrosis occurs in arterial walls.

9. Acute Rejection:
 This may occur within days of transplantation in
untreated recipient , or may appear months or even
years later after immunosuppression has been
terminated.
 acute graft rejection is a combined process in which
both cellular and humoral tissue injuries contribute.
 Histologically, humoral rejection is associated with
vasculitis, whereas cellular rejection is marked by
interstitial mononuclear cell infiltrate.

10. Chronic Rejection:
 In recent years, acute rejection has been significantly
controlled by immunosuppressive therapy, and
chronic rejection has become an important cause
of graft failure.
 Patients with chronic rejection present clinically with
progressive rise in serum creatinine over a period
of 4 to 6 months.
 Chronic rejection is dominated by vascular changes,
interstitial fibrosis, and tubular atrophy with loss of
renal parenchyma .
 The vascular changes consist of dense, obliterative
intimal fibrosis, principally in renal cortical arteries.

11. Transplantation of Hematopoietic Cells :
 Use of hematopoietic cell transplants for:
hematologic malignancies;
certain nonhematologic cancers;
aplastic anemias; and
certain immunodeficiency states.
 Hematopoietic stem cells are usually obtained
from bone marrow , but may also be harvested
from peripheral blood after they are mobilized
from bone marrow by administration of
hematopoietic growth factors.

12.  In most conditions in which bone marrow
transplantation is indicated, the recipient is
irradiated with lethal doses or receive
chemotherapy either to destroy the malignant
cells (e.g., leukemias) ; or to create a graft bed
(e.g., aplastic anemias).
 Three major problems arise in bone marrow
transplantation:
Graft-versus-host (GVH) disease
Transplant rejection
Immunodeficiency

13. GVH disease:
 occurs in any situation in which immunologically
competent cells or their precursors of donor
are transplanted into immunologically crippled
recipients.
 the transferred cells recognize alloantigens in
the recipients .
 GVH disease occurs most commonly in setting
of allogeneic bone marrow transplantation; but
may also follow transplantation of solid organs
rich in lymphoid cells (e.g., liver) .

14.  Recipients of bone marrow transplants are
immunodeficient because of either their primary
disease or prior treatment of disease with drugs
or irradiation.
 When such recipients receive normal bone
marrow cells from allogeneic donors,
the immunocompetent T- cells present in donor
marrow recognize recipient's HLA antigens
as foreign and react against them.
 Both CD4+ and CD8+ T cells recognize and attack
the recipient's tissues.

15. Acute GVH disease:
 occurs within days to weeks after allogeneic bone
marrow transplantation.
 Although any organ may be affected, the major clinical
manifestations result from involvement of epithelia
of skin, liver, and intestines.
 Involvement of skin in GVH disease is manifested by
a generalized rash.
 Destruction of small bile ducts gives rise to jaundice.
 Mucosal ulceration of the gut results in bloody
diarrhea.

16. Chronic GVH disease:
 may follow the acute syndrome or may occur
insidiously.
 These patients have extensive cutaneous injury, with
destruction of skin appendages and fibrosis of dermis.
The changes may resemble systemic sclerosis .
 Chronic liver disease manifested by cholestatic
jaundice .
 Damage to gastrointestinal mucosa may cause
esophageal strictures.

17. Transplant rejection:
 The mechanisms responsible for rejection of
allogeneic bone marrow transplants are poorly
understood.
 It seems to be mediated by NK cells and T cells that
survive in the irradiated recipient.
Immunodeficiency:
 Is a frequent accompaniment of GVH disease.
 Affected individuals are profoundly
immunosuppressed and are easily infected.
 Although many organisms may infect patients,
infection with cytomegalovirus is particularly
important. Cytomegalovirus-induced pneumonitis
can be fatal .

18. THANK YOU