Patterns and Mechanisms of Graft Rejection

Slide 1 · Patterns and mechanisms of graft rejection

Alloimmune recognition, renal allograft morphology, and mechanisms of graft failure

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish hyperacute, acute, and chronic rejection by mechanism and pathology.

Explain direct and indirect allorecognition and their effector pathways.

Recognize the principal renal allograft patterns: Tubulitis, arteritis, capillary injury, and fibrosis.

Connect morphology to temporal context and implications for graft function.

Slide 3 · Rejection is an alloimmune attack on the graft

The recipient identifies transplanted tissue as foreign.

T lymphocytes and antibodies against graft antigens injure the transplanted organ.

The resulting damage may affect graft parenchyma, blood vessels, or both.

Anatomic injury patterns reflect the dominant immune mechanism.

Slide 4 · Allograft and xenograft are different settings

Allograft

Donor and recipient are of the same species.

The focus of standard clinical graft-rejection pathology.

Recipient responses to donor alloantigens are central.

Xenograft

Donor and recipient are different species.

Distinct antigenic barriers may apply.

Not the focus of the textbook morphology discussion.

Slide 5 · HLA polymorphism drives donor–recipient disparity

Highly polymorphic HLA genes

Different donor and recipient HLA alleles

Alloantigens recognized as foreign

Activation of recipient lymphocytes

Exception: Identical twins generally lack these major HLA differences.

Slide 6 · Why allografts provoke strong T-cell responses

Alloreactive T-cell precursors occur at unusually high frequency.

The response to an allograft can exceed responses mounted against microbes.

Without immune suppression, a vigorous response may rapidly destroy tissue.

The intensity of allorecognition explains the need for potent immunosuppression.

Slide 7 · Direct pathway of alloantigen recognition

Donor

Graft antigen-presenting cell

Recipient

Alloreactive T lymphocyte

Intact donor HLA

Donor APC displays alloantigen directly

Graft antigen-presenting cells display donor HLA directly to recipient T cells.

The pathway is especially relevant to cytotoxic T-cell responses in acute rejection.

Slide 8 · Indirect pathway of alloantigen recognition

Recipient

Antigen-presenting cell

Recipient

Alloreactive T lymphocyte

Donor antigen

Processed peptide + self HLA

Host APC processes donor alloantigen

Host antigen-presenting cells take up and process graft alloantigens.

Peptides are presented to host T cells on recipient HLA.

Slide 9 · Direct and indirect pathways differ mechanistically

Direct recognition

Antigen-presenting cell comes from the donor graft.

Intact donor HLA is recognized by recipient T cells.

May be particularly important in CTL-mediated acute rejection.

Indirect recognition

Recipient antigen-presenting cell processes graft antigen.

Antigen is presented in a conventional peptide–HLA context.

May have a greater role in chronic rejection.

Relative contributions are described as tendencies, not exclusive assignments.

Slide 10 · CD8+ and CD4+ cells provide distinct effector functions

CD8+ T lymphocytes

Differentiation into cytotoxic T lymphocytes.

Direct destruction of graft cells.

A major effector of acute cellular rejection.

CD4+ T lymphocytes

Predominantly cytokine-producing effector cells, especially Th1.

Recruitment and activation of inflammatory cells.

Contribution to graft inflammation and chronic remodeling.

Slide 11 · B-cell alloimmunity generates donor-reactive antibody

B cells recognize graft antigens

T-cell help supports B-cell activation

Antibodies to donor HLA are produced

Alloantibodies target graft tissue

Alloantibodies can cause endothelial injury in acute and chronic rejection.

Slide 12 · Two effector arms converge on graft injury

Cellular arm

CD8+ cytotoxic lymphocytes kill graft cells.

CD4+ cells produce inflammatory cytokines.

Interstitial and vascular cellular injury may follow.

Humoral arm

Alloantibodies bind graft vascular antigens.

Complement activation amplifies endothelial injury.

Capillary injury and thrombosis may follow.

Both arms may operate in the same transplanted organ.

Slide 13 · Classification links mechanism to pathologic pattern

Clinical tempo and graft dysfunction

Dominant cellular or antibody-mediated injury

Anatomic lesion on graft examination

Hyperacute, acute, or chronic pattern

This historical framework was developed chiefly from kidney allografts.

Slide 14 · Three classic rejection patterns at a glance

Pattern

Typical tempo

Dominant mechanism

Major lesion

Hyperacute

At reperfusion / immediately

Preformed antibody

Thrombosis and ischemic necrosis

Acute

Days to weeks; sometimes later

T cells and/or antibodies

Tubulitis, arteritis, capillary injury

Chronic

Months to years

Chronic T-cell effects + alloantibodies

Vascular narrowing and fibrosis

Slide 15 · Elapsed time helps, but does not define the mechanism

Immediately

Hyperacute antibody injury at restored perfusion

Days / weeks

Acute rejection is often an early complication

Months / years

Chronic progressive remodeling emerges

Acute rejection can arise much later if immunosuppression is reduced or stopped.

Slide 16 · The microvasculature is a recurrent target

Circulating antibodies contact donor vascular endothelium immediately.

Complement activation can injure endothelial surfaces.

Vascular damage promotes thrombosis or long-term remodeling.

Parenchymal dysfunction may therefore result from impaired perfusion.

Slide 17 · Hyperacute rejection requires pre-existing antibody

Anti–blood-group antibody

Naturally occurring IgM can recognize graft blood-group antigens.

ABO incompatibility produces an immediate vascular target.

Anti-HLA alloantibody

Antibody can arise after exposure to allogeneic cells.

Donor HLA on vascular cells becomes a target after reperfusion.

Slide 18 · Prior exposure can sensitize a recipient

Blood transfusion

Pregnancy

Prior organ transplantation

Each exposure can introduce allogeneic cells and induce anti-HLA antibodies.

Preformed anti-donor antibody changes risk at the next transplant.

Slide 19 · Hyperacute injury begins when blood flow resumes

Reperfusion of the graft

Preformed antibody binds endothelium

Complement activation

Endothelial injury and thrombosis

Graft ischemia / necrosis

The initiating antibody is present before implantation.

Slide 20 · Antibody binding triggers vascular thrombosis

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Platelet–fibrin thrombus

Vascular wall / endothelium

Antibody–endothelial binding activates complement.

Endothelial disruption promotes platelet–fibrin thrombi and ischemic damage.

Slide 21 · Hyperacute rejection has a dramatic gross phenotype

The transplanted kidney rapidly becomes cyanotic and mottled.

Perfusion failure is accompanied by abrupt loss of urine production.

The injury begins almost immediately after implantation and reperfusion.

Gross changes reflect widespread vascular occlusion and ischemia.

Slide 22 · Small arteries show fibrinoid necrosis and occlusion

Acute arterial and arteriolar wall injury may become fibrinoid.

Platelet–fibrin thrombi narrow or obstruct vascular lumens.

The vascular injury mechanism predicts rapid tissue ischemia.

The lesion is not primarily a slow process of fibrosis.

Slide 23 · Hyperacute glomerular injury is thrombotic

Capillary thrombi

Schematic: Capillary loops (not histology)

Glomerular capillaries may undergo thrombotic occlusion.

Neutrophils also accumulate in glomeruli and small graft vessels.

Slide 24 · Ischemia progresses toward cortical infarction

Arteriolar and arterial thrombosis

Glomerular capillary occlusion

Severe perfusion loss

Renal cortical infarction

Established hyperacute injury renders the graft nonfunctional.

Slide 25 · Hyperacute injury is often irreversible

Severe endothelial injury rapidly compromises essentially the entire graft.

Diffuse thrombosis culminates in necrotic kidney cortex.

An affected kidney as nonfunctional and requiring removal.

Pretransplant antibody prevention is therefore essential.

Slide 26 · ABO compatibility and crossmatch are preventive safeguards

Compatible blood-group selection

Test for antibodies to proposed donor cells

Avoid preformed antibody–target pairing

Markedly lower hyperacute risk

The textbook attributes rarity of hyperacute rejection to ABO matching and crossmatch screening.

Slide 27 · Case: Immediate anuria following reperfusion

Clinical / pathologic vignette

A kidney becomes mottled and cyanotic almost as soon as vascular clamps are removed. Urine output ceases. The vascular lesions consist of extensive platelet–fibrin thrombi.

Most likely rejection pattern?

1. Hyperacute antibody-mediated rejection

2. Acute T-cell–mediated rejection

3. Chronic graft arteriosclerosis

Teaching vignette; Not patient-derived clinical data

Slide 28 · Hyperacute pattern: Explain the discriminating evidence

Immediate onset after restored perfusion is a defining temporal clue.

Preformed anti-endothelial antibody explains rapid complement activation.

Diffuse intravascular thrombi account for mottling and anuria.

The central lesion is acute ischemic injury, not established intimal fibrosis.

Slide 29 · Acute rejection may appear early or after later tapering

Typical appearance: Days to weeks after transplantation.

It is an important cause of early graft failure.

A later episode can occur abruptly when immunosuppression is reduced or stopped.

Time alone cannot exclude an acute immune lesion.

Slide 30 · Acute rejection is mechanistically heterogeneous

Acute cellular rejection

Alloreactive CD8+ and CD4+ T lymphocytes.

Direct parenchymal killing and inflammatory recruitment.

Tubulointerstitial or vascular lesions.

Acute antibody-mediated rejection

Antibodies reactive with vascular alloantigens.

Classical complement activation.

Glomerular and small-vessel injury.

Many rejecting grafts show more than one mechanism.

Slide 31 · Cytotoxic T cells can directly injure graft cells

Alloantigen recognition

Activation of graft-reactive CD8+ T cells

Differentiation to cytotoxic effector cells

Direct injury of graft parenchymal cells

CTL-mediated cell killing is part of acute T cell–mediated rejection.

Slide 32 · CD4+ T cells amplify rejection through cytokines

Activated graft-reactive CD4+ cells

Effector cytokine production

Recruitment of leukocytes

Interstitial inflammation and tissue injury

CD4+ cytokine effects and CD8+ direct killing as complementary mechanisms.

Slide 33 · Acute cellular rejection has two morphologic patterns

Tubulointerstitial

Interstitial lymphocytic inflammation.

Tubulitis: Inflammatory cells between tubular epithelial cells.

Focal tubular cell injury.

Vascular

Inflammation involving vessels.

Swollen endothelium and lymphocytes in the intima.

Sometimes vascular wall necrosis.

Slide 34 · Tubulitis: Inflammatory cells within tubular epithelium

Tubular epithelium

Lymphocytes within tubular epithelium

Schematic: Section of one renal tubule

Tubulitis signifies lymphocytes entering and lying among epithelial cells of renal tubules.

Concurrent interstitial inflammation and tubular injury are typical.

Slide 35 · Interstitial inflammation is T-cell rich

Activated CD4+ and CD8+ T cells populate the interstitium.

The infiltrate is accompanied by focal tubular injury.

Inflammation outside tubules plus tubulitis defines the tubulointerstitial pattern.

The finding is rooted in T cell–mediated cytotoxic and cytokine effects.

Slide 36 · Intimal arteritis locates the immune attack in vessels

Lymphocytes beneath endothelium

Vascular wall / endothelium

Lymphocytes are present between the vessel endothelium and the vessel wall.

Robbins also uses the term endotheliitis for this lesion.

Slide 37 · Vascular cellular rejection may damage vessel walls

Vessel endothelium becomes swollen during immune attack.

Lymphocytes may undermine or traverse the endothelial layer.

Some lesions advance to necrosis of vessel walls.

Recognition of this pattern distinguishes vascular injury from isolated tubular inflammation.

Slide 38 · Why identifying cellular rejection matters clinically

Acute cellular rejection is specifically susceptible to T-cell-directed immunosuppression.

Many cases without concomitant humoral rejection respond well.

An antibody-mediated component changes the mechanistic interpretation.

Recognition of both patterns is important for therapeutic planning.

Slide 39 · Acute humoral rejection begins on the endothelium

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Capillary inflammation

Vascular wall / endothelium

Antibodies bind the vascular endothelium and activate complement via the classical pathway.

The result is vascular inflammation and endothelial injury.

Slide 40 · Classical complement activation leaves a C4d footprint

Antibody binds graft endothelium

Classical complement pathway activates

Complement products accumulate

C4d may be demonstrable in capillaries

C4d deposition is described in glomerular and peritubular capillary locations.

This is a mechanistic marker, not a standalone classification algorithm.

Slide 41 · Antibody-mediated injury centers on capillaries

Glomerular inflammation is a typical feature.

Peritubular capillaries may show inflammatory cell accumulation.

Complement products, including C4d, may deposit in affected sites.

Small-vessel thrombosis can accompany the capillary lesion.

Slide 42 · Glomerulitis represents intraglomerular inflammation

Glomerular capillary inflammation

Schematic: Capillary loops (not histology)

Glomerular inflammation as a characteristic of acute antibody-mediated rejection.

The schematic depicts involvement of small capillary structures without simulating microscopy.

Slide 43 · Peritubular capillaritis signals microvascular injury

Peritubular capillaries are a second major site of humoral graft injury.

Inflammatory accumulation follows antibody- and complement-related endothelial activation.

Associated capillary C4d deposition supports complement engagement.

Interpret capillary inflammation together with the overall graft pattern.

Slide 44 · A vascular thrombus can also occur in acute humoral injury

Antibody-mediated endothelial injury is not limited to leukocyte accumulation.

Small vessels may develop focal thrombi.

Compared with hyperacute rejection, the setting need not involve preformed antibody at immediate reperfusion.

The same vascular target can yield a different clinical tempo.

Slide 45 · Cellular versus humoral acute rejection: Tissue clues

Finding

T cell–mediated

Antibody-mediated

Tubulitis

Characteristic

Not emphasized as primary lesion

Intimal arteritis

Characteristic vascular pattern

Vascular injury may coexist

Glomerular / peritubular capillaritis

Not defining pattern in this account

Characteristic microvascular pattern

C4d deposits

Not a central mechanistic feature

Reflect classical complement activation

Predominant target

Parenchyma and vessels

Glomeruli and small vessels

Slide 46 · Mixed rejection is common

Cellular and antibody-mediated injury are separate explanatory categories.

Most rejecting grafts may exhibit both patterns.

A biopsy can therefore include tubular, vascular, and capillary abnormalities.

Do not presume a single effector pathway explains every lesion.

Slide 47 · Case: Tubulitis with intimal lymphocytes

Clinical / pathologic vignette

Several weeks after kidney transplantation, graft dysfunction develops. A biopsy shows interstitial T-cell infiltrates, lymphocytes between tubular epithelial cells, and lymphocytes beneath arterial endothelium.

Which mechanism dominates?

1. Acute T-cell–mediated rejection

2. Hyperacute preformed-antibody rejection

3. Chronic rejection alone

Teaching vignette; Not patient-derived clinical data

Slide 48 · Case explanation: Two cellular compartments

Tubulitis demonstrates direct inflammatory involvement of tubular epithelium.

Intimal lymphocytes identify the vascular form of cellular rejection.

The coexistence of both lesions is compatible with acute T-cell–mediated rejection.

Additional evidence would be needed to characterize any simultaneous humoral lesion.

Slide 49 · Case: Capillary inflammation with C4d

Clinical / pathologic vignette

A renal allograft biopsy shows inflammation of glomeruli and peritubular capillaries. Complement-product deposition, including C4d, is demonstrated in the microvasculature.

Which effector pathway is suggested?

1. Antibody with classical complement activation

2. Exclusive CTL-mediated tubular injury

3. Only chronic smooth-muscle proliferation

Teaching vignette; Not patient-derived clinical data

Slide 50 · Case explanation: Link C4d to the mechanism

Glomerular and peritubular capillary injury identify the microvascular compartment.

C4d deposition is consistent with activation of the classical complement pathway.

The combination is characteristic of acute antibody-mediated injury.

Complement deposition should be interpreted with the morphologic setting.

Slide 51 · Chronic rejection is progressive, not explosive

Graft dysfunction evolves insidiously over months or years.

The principal pathologic themes are vascular narrowing and parenchymal scarring.

Both T-cell effects and alloantibodies are implicated.

The injury becomes increasingly resistant to reversal with therapy.

Slide 52 · Chronic T-cell cytokines drive structural remodeling

Persistent graft-reactive T-cell responses

Cytokines act on local tissue

Smooth-muscle / fibroblast activation

Intimal thickening and interstitial fibrosis

These cells as believed to be key drivers; This is not an exclusive mechanism.

Slide 53 · Alloantibodies also contribute to chronic rejection

The chronic lesion is not explained by T lymphocytes alone.

Donor-reactive antibody may sustain vascular endothelial injury.

Repeated endothelial damage helps account for chronic glomerular changes.

The result is cumulative microvascular and parenchymal remodeling.

Slide 54 · Graft arteriosclerosis progressively narrows the lumen

Intimal thickening narrows the lumen

Vascular wall / endothelium

Intimal thickening progressively reduces available lumen diameter.

This native vector diagram is schematic, not a specimen image.

Slide 55 · Chronic vascular narrowing links immunity to ischemia

Persistent alloimmune vascular injury

Intimal proliferation and thickening

Progressive luminal narrowing

Reduced perfusion and graft tissue loss

Structural vascular changes help explain chronic parenchymal atrophy and fibrosis.

Slide 56 · Transplant glomerulopathy involves basement-membrane duplication

Duplication of capillary basement membranes

Schematic: Capillary loops (not histology)

Chronically rejecting kidney grafts can develop duplication of glomerular basement membranes.

Robbins relates this finding to chronic endothelial injury.

Slide 57 · Peritubular capillary basement membranes also remodel

Chronic capillary damage may lead to multilayered basement membranes.

Peritubular capillaritis can accompany this microvascular remodeling.

The lesion fits the broader theme of repeated endothelial injury.

It differs from immediate thrombotic occlusion of hyperacute rejection.

Slide 58 · Tubular atrophy and interstitial fibrosis replace parenchyma

Preserved tubule

Atrophic tubule

Marked atrophy

Interstitial fibrous matrix replaces functioning parenchyma

Schematic: Relative tubular atrophy

Chronic kidney allografts develop tubular atrophy with interstitial fibrosis.

These changes may occur secondary to vascular lesions and parenchymal loss.

Slide 59 · Chronic rejection may contain little visible inflammation

Interstitial mononuclear infiltrates are often sparse in chronic rejection.

Established scarring and vascular remodeling can dominate the biopsy.

Sparse inflammation does not exclude a prior or ongoing immune contribution.

Pathologic interpretation must assess structural damage as well as leukocyte density.

Slide 60 · Chronic pathology is the cumulative outcome of injury

Chronic cellular and humoral stress

Persistent endothelial injury

Intimal and basement-membrane remodeling

Tubular atrophy + interstitial fibrosis

This is a conceptual synthesis of Robbins morphology, not a validated clinical scoring pathway.

Slide 61 · Chronic rejection: Major tissue compartments

Compartment

Prominent change

Pathogenetic implication

Arteries

Intimal thickening / occlusion

Long-standing vascular remodeling

Glomeruli

Basement-membrane duplication

Chronic endothelial injury

Peritubular capillaries

Capillaritis; BM multilayering

Sustained capillary damage

Tubules / interstitium

Atrophy and fibrosis

Progressive parenchymal loss

Slide 62 · Chronic rejection is difficult to reverse

Control of acute rejection has improved early transplant outcomes.

Chronic rejection remains refractory to most available therapies.

The lesion consists substantially of fixed vascular and fibrotic remodeling.

It is an increasingly important cause of late graft failure.

Slide 63 · Case: Slowly progressive graft dysfunction

Clinical / pathologic vignette

Several years after kidney transplantation, graft function gradually declines. A biopsy demonstrates diffuse intimal thickening, duplication of glomerular basement membranes, interstitial fibrosis, and tubular atrophy.

Most consistent pattern?

1. Chronic allograft rejection

2. Hyperacute rejection

3. Isolated acute tubulitis

Teaching vignette; Not patient-derived clinical data

Slide 64 · Case explanation: Structural injury predominates

Gradual deterioration over years is consistent with chronic rejection.

Intimal thickening identifies graft arteriosclerosis.

Glomerular basement-membrane duplication suggests chronic endothelial injury.

Fibrosis and tubular atrophy account for progressive nephron loss.

Slide 65 · Anatomical localization sharpens interpretation

Dominant site

Principal lesion

Mechanistic association

Renal tubules

Tubulitis

Acute T-cell effect

Arterial intima

Endotheliitis / intimal arteritis

Acute cellular vascular injury

Glomerular / peritubular capillaries

Capillaritis with C4d

Acute antibody + complement

Small-vessel lumen

Thrombi at reperfusion

Hyperacute antibody injury

Vessel wall and interstitium

Intimal thickening + fibrosis

Chronic remodeling

Slide 66 · The same vascular target produces distinct patterns

Immediately

Preformed antibody.

Complement, widespread thrombi.

Severe ischemic necrosis.

Acute episode

Graft-reactive antibody and/or T cells.

Capillaritis or intimal arteritis.

Potentially reversible inflammation.

Long term

Ongoing cellular and antibody effects.

Intimal thickening; Basement-membrane remodeling.

Progressive fibrosis.

Slide 67 · Morphology is interpreted with mechanism and tempo

Observe site and type of injury

Integrate time course

Infer likely cellular / humoral mechanism

Classify classic rejection pattern

This is an educational approach—not a substitute for contemporary organ-specific diagnostic criteria.

Slide 68 · Organ effects vary; The immune principles recur

Detailed rejection morphology primarily for the kidney.

Allografts of heart, lungs, liver, and pancreas also experience rejection.

Cellular attack, endothelial antibody injury, and chronic remodeling are broad mechanisms.

Organ-specific lesion definitions require organ-specific reference material.

Slide 69 · Immunosuppression preferentially limits acute T-cell responses

Alloreactive T-cell activation

T-cell proliferation / effector function

Acute cellular graft injury

Suppression of immune activation

Current drugs are described as principally designed to reduce acute rejection by limiting T-cell responses.

Slide 70 · Calcineurin blockade interrupts T-cell cytokine signaling

Tacrolimus or cyclosporine

Calcineurin inhibited

NFAT signaling reduced

IL-2 transcription reduced

T-cell response suppressed

Tacrolimus and cyclosporine inhibit calcineurin, reducing NFAT-dependent T-cell activation.

This is a simplified explanation from the adjacent graft-survival section.

Slide 71 · Graft protection requires balancing immune suppression

Prevent rejection

HLA matching can benefit kidney grafts.

Immunosuppressive agents suppress alloreactive responses.

Additional therapies target antibody-mediated injury.

Recognize tradeoffs

Susceptibility to opportunistic infection rises.

Viral reactivation can damage a transplant.

Risk of some malignancies also increases.

These are implications from the adjacent Robbins section on graft survival.

Slide 72 · Three mechanism–morphology chains to retain

Rejection pattern

Immune initiating event

Diagnostic tissue consequence

Hyperacute

Preformed antibody + complement

Thrombosis → infarction

Acute cellular

Activated CD8+/CD4+ cells

Tubulitis / arteritis

Acute humoral

Endothelial alloantibody + complement

Glomerulitis / capillaritis ± C4d

Chronic

Persistent cellular and antibody injury

Arteriosclerosis / fibrosis

Slide 73 · Apply the framework: Three contrasting presentations

At reperfusion

Pre-existing antibody.

Thrombi in small vessels.

Abrupt graft failure.

Weeks after grafting

Tubulitis or microvascular inflammation.

T-cell and/or antibody effects.

Potential for treatment response.

Years after grafting

Intimal narrowing and glomerular remodeling.

Interstitial fibrosis and atrophy.

Progressive loss of function.

Slide 74 · Summary: Immunologic mechanism predicts the lesion

Preformed antibody → complement and thrombosis → hyperacute ischemic necrosis.

T cells → tubulitis and/or arteritis → acute cellular rejection.

Alloantibody → complement and capillary injury → acute humoral rejection.

Persistent alloimmune injury → vascular remodeling and fibrosis → chronic rejection.

Slide 75 · Primary reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Chapter 6: Diseases of the Immune System.

Primary teaching section: Patterns and Mechanisms of Graft Rejection.

Parent context: mechanisms of allograft recognition; adjacent section: graft-survival strategies.

Morphology is presented for renal allografts; schematic illustrations are not diagnostic photomicrographs.