Transplantation of Hematopoietic Stem Cells

Slide 1 · Transplantation of

Hematopoietic Stem Cells

Mechanisms, graft-versus-host disease, and immune complications

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why hematopoietic stem cells can restore hematopoiesis after conditioning.

Trace donor T-cell recognition to acute and chronic graft-versus-host disease.

Relate characteristic organ pathology to clinical manifestations and infection risk.

Emphasis: Mechanism → morphology → clinicopathologic interpretation.

Slide 3 · Why hematopoietic stem cell transplantation matters

Transplanted hematopoietic stem cells (HSCs) can establish new marrow hematopoiesis.

Use in hematologic malignancy, marrow failure and inherited disorders.

Success requires engraftment, while immune complications may limit recovery.

The therapeutic graft is a living hematopoietic and immune-cell system.

Slide 4 · Major indications

Indication group

Examples from the source

Transplantation goal

Hematologic malignancy

Hematologic cancers

Reconstitute hematopoiesis in a treated host

Marrow failure

Aplastic anemia

Restore hematopoietic cell production

Inherited marrow disease

Sickle cell anemia; thalassemia

Provide a new hematopoietic system

Inherited immune defect

Immunodeficiency states

Restore defective immune-cell production

Examples are the textbook’s; The list is not an eligibility guideline.

Slide 5 · Malignancy: The marrow is both target and substrate

HSC transplantation is used to treat hematologic malignancies.

Pretransplant treatment can deplete host cells and create marrow space.

Transferred cells must engraft and regenerate blood-forming cells.

Graft-versus-leukemia control is relevant when considering donor T-cell depletion.

Slide 6 · Marrow failure: Replacing deficient hematopoiesis

Aplastic anemia is an explicit example of a marrow failure indication.

The transplanted HSC population must populate recipient marrow niches.

Engraftment offers a route toward sustained hematopoietic output.

Core distinction: Correcting a deficient blood-forming compartment.

Slide 7 · Inherited erythroid disorders

Sickle cell anemia and thalassemia are listed as inherited marrow-disorder indications.

The therapeutic target is the hematopoietic lineage that produces circulating blood cells.

Successful graft function depends on stem-cell survival and proliferation.

Indications; It does not prescribe patient selection criteria.

Slide 8 · Inherited immunodeficiency states

Some inherited immunodeficiencies can be approached by HSC transplantation.

Corrected hematopoietic progenitors can contribute to immune-cell reconstitution.

Immune reconstitution itself may be delayed after the transplant.

Restoration of immunity is both a treatment goal and a post-transplant vulnerability.

Slide 9 · Genetically reengineered HSC transplantation

Affected patient

Obtain hematopoietic stem cells

Cell modification

Genetically reengineer the harvested cells

Return cells

Transplant altered cells into the patient

Repopulation

New hematopoietic cell progeny develop

This approach in selected immunodeficiencies and inherited marrow disorders; No specific vector or gene is specified.

Slide 10 · HSC procurement: Historical and current sources

Historical source

Bone marrow was the conventional HSC collection site.

It remains a source of transplantable hematopoietic cells.

Other sources emphasized

Mobilized peripheral blood is now commonly used.

Newborn umbilical cord blood is rich in HSCs.

The source distinguishes procurement methods, not comparative clinical outcomes.

Slide 11 · Mobilizing HSCs into peripheral blood

Marrow HSCs

Stem cells reside in bone marrow

Growth factors

Mobilization follows administered growth factors

Peripheral blood

HSCs enter circulating blood

Harvest

Peripheral collection supplies the graft

Mobilization is a procurement step, not equivalent to engraftment.

Slide 12 · Umbilical cord blood as an HSC source

Umbilical cord blood from newborn infants contains many HSCs.

It provides an alternative to harvest from bone marrow or mobilized blood.

The choice of source precedes the distinct process of recipient conditioning.

The supplied excerpt does not quantify cell doses, success rates or collection trade-offs.

Slide 13 · Three graft sources: What the textbook states

Source

Source description

Specific text-supported feature

Bone marrow

Direct marrow collection

Historically used for HSC transplantation

Peripheral blood

Collection after mobilization

Growth factors mobilize HSCs from marrow

Umbilical cord blood

Blood of newborn infants

Rich source of HSCs

No comparative engraftment kinetics or GVHD rates are provided in the source.

Slide 14 · Transplantation as a sequential process

Procure

Obtain HSCs from the selected source

Condition

Deplete recipient cells

Infuse

Transfer harvested HSCs

Engraft

Cells establish within marrow niches

An explanatory sequence distilled from the source; Not a detailed clinical protocol.

Slide 15 · Recipient conditioning

Irradiation or chemotherapy is used in most indications described.

Treatment depletes host cells before HSC transplantation.

This also contributes to the immunodeficiency that follows transplantation.

Conditioning has a desired marrow effect and an important immune cost.

Slide 16 · Why conditioning improves engraftment

Host-cell depletion

Remove competing recipient cells

Available niches

Open space in the marrow microenvironment

Donor HSC entry

Transplanted cells enter permissive niches

Cell advantage

Promote donor HSC survival and proliferation

The marrow niche is part of the mechanism; Transplant success is not merely cell infusion.

Slide 17 · Conditioning: Intended effect versus cost

Intended effect

Makes niches available for transplanted HSCs.

Favors survival and proliferation of the graft.

Immunologic cost

Myeloablation depletes recipient leukocytes.

Lymphodepletion contributes to infection susceptibility.

The same intervention permits engraftment and creates vulnerability.

Slide 18 · Engraftment is a microenvironmental event

HSCs require marrow niches that support stem-cell persistence.

Depleting host cells reduces competition within these niches.

Donor cells then have an opportunity for survival and proliferation.

A successful graft must establish a continuing source of hematopoiesis.

Slide 19 · The two signature complications

Graft-versus-host disease (GVHD): Donor-derived immune cells attack host tissues.

Immunodeficiency: Host defense is impaired during and after transplantation.

Both are linked to the immune biology of the HSC graft and its recipient.

These two complications receive special emphasis in the Robbins section.

Slide 20 · GVHD: Immunologic direction of attack

Donor inoculum

Contains immunocompetent T lymphocytes

Recipient host

Immunologically compromised

Recognition

Donor cells perceive host alloantigens

Tissue injury

Host epithelia and other targets are attacked

Unlike host-mediated graft rejection, GVHD proceeds from graft immune cells toward the host.

Slide 21 · Necessary setting for GVHD

The transferred graft contains competent immune cells or their precursors.

The host cannot adequately eliminate the transferred immune cells.

The graft’s immune cells recognize host antigens and react.

The transplant contains the effector system causing tissue injury.

Slide 22 · Directionality: Rejection versus GVHD

Solid-organ graft rejection

Host immune responses recognize graft alloantigens.

The transplanted organ is the primary target.

Graft-versus-host disease

Donor-derived T lymphocytes recognize host alloantigens.

Recipient organs become targets of donor-cell attack.

Same principle—alloantigen recognition; Opposite direction of injury.

Slide 23 · GVHD outside conventional HSC transplantation

GVHD is seen most commonly following HSC transplantation.

Robbins also describes rare GVHD after lymphoid-cell-rich solid organs, such as liver.

Transfusion of unirradiated blood is another rare setting.

The critical transferable component is immunologically active donor lymphocytes.

Slide 24 · Allogeneic grafts carry immunocompetent donor cells

Allogeneic HSC preparations may include donor T lymphocytes.

Donor T cells can recognize recipient HLA molecules as foreign.

This alloimmune response initiates injury of recipient tissues.

Donor T cells are central effectors, not incidental graft contamination.

Slide 25 · From donor HLA recognition to organ damage

Host HLA

Recipient HLA differs from donor HLA

Donor T cells

Alloreactive donor T lymphocytes respond

Effector response

Cytotoxicity and cytokine release

Organ injury

Damage to host epithelial compartments

Flow is conceptual: Direct cytotoxicity and cytokine-mediated tissue injury.

Slide 26 · HLA matching mitigates the alloimmune problem

Donor and recipient HLA alleles are matched as closely as practicable.

Robbins specifies DNA sequencing–based molecular typing of HLA alleles.

The purpose is to minimize donor T-cell recognition of the recipient.

High-resolution typing addresses the immunologic source of alloreactivity.

Slide 27 · Classification of GVHD in the Robbins section

Form

Textbook temporal framing

Main characteristic injury

Acute GVHD

Days to weeks after allogeneic HSC transplant

Skin, small bile ducts and intestinal epithelia

Chronic GVHD

May follow acute disease or arise insidiously

Fibrosing skin injury, cholestatic liver injury, GI and immune damage

Do not substitute a rigid numerical acute/chronic cutoff; None is given in this excerpt.

Slide 28 · Acute GVHD: Early donor-cell–mediated injury

Acute GVHD develops within days to weeks after allogeneic transplantation.

Targeted injury is especially prominent in epithelial tissues.

Severity of tissue damage does not require a dense lymphocytic infiltrate.

Early presentation plus epithelial injury links mechanism to morphology.

Slide 29 · Acute GVHD: The major organ pattern

Target

Pathologic process

Clinical expression

Skin

Lymphocytic infiltration; keratinocyte apoptosis

Rash beginning at characteristic sites

Small bile ducts

Immune-mediated epithelial destruction

Jaundice

Intestinal mucosa

Mucosal injury and ulceration

Bloody diarrhea

The three manifestations represent injury to different epithelial compartments.

Slide 30 · Two complementary mechanisms of acute injury

Allorecognition

Donor T cells respond to host antigens

Direct effect

CD8+ T-cell cytotoxicity

Indirect effect

Cytokines released by sensitized T cells

Outcome

Severe epithelial damage

The source attributes considerable damage to cytokines in addition to direct killing.

Slide 31 · Why severe damage can coexist with sparse infiltrates

Acute GVHD lesions are often not densely infiltrated by lymphocytes.

Effector T cells can injure targets directly through cytotoxicity.

Released cytokines can amplify tissue damage beyond visible cellular numbers.

Do not exclude acute GVHD simply because biopsy inflammation appears sparse.

Slide 32 · Acute cutaneous GVHD: Rash distribution

Rash may first appear on neck and ears.

Palms and soles are also characteristic early sites in the source.

The eruption can subsequently become generalized.

A distinct early distribution can precede more widespread skin involvement.

Slide 33 · Acute skin GVHD: Epithelial interface injury

Epidermis

Dermis

Interface vacuoles + sparse lymphocytes

SCHEMATIC (not a histologic specimen)

Sparse lymphocytes are present near the dermoepidermal junction.

Small spaces or vacuoles develop at the dermoepidermal interface.

Original schematic based on the supplied description of Fig. 6.36A–B.

Slide 34 · Acute skin GVHD: Keratinocyte apoptosis

Epidermis

Dermis

Interface vacuoles + sparse lymphocytes

SCHEMATIC (not a histologic specimen)

Apoptotic keratinocytes are an important biopsy feature.

Damaged cells may display abnormal keratin staining (dyskeratosis).

Original schematic—not an H&E specimen or a reproduction of the Robbins image.

Slide 35 · Acute skin GVHD: Altered epidermal maturation

Epidermis

Dermis

Interface vacuoles + sparse lymphocytes

SCHEMATIC (not a histologic specimen)

Disorganization of keratinocyte maturation.

The pattern accompanies interface damage and cell death.

A morphologic combination is more informative than any single finding.

Slide 36 · Acute skin GVHD: Integrating clinical and biopsy clues

A characteristic rash establishes the clinical context.

Biopsy may show sparse junctional lymphocytes, basal vacuoles and apoptotic cells.

Clinical and pathologic findings must be interpreted together.

The supplied figure caption is descriptive; No validated diagnostic threshold is given.

Slide 37 · Acute liver GVHD: Biliary epithelial injury

Immune attack

Alloreactive graft-derived effectors

Duct damage

Destruction of small bile ducts

Bile flow injury

Cholestatic dysfunction

Clinical result

Jaundice

The source describes bile duct destruction as the substrate for jaundice.

Slide 38 · Acute intestinal GVHD: Explaining diarrhea

Mucosal target

Donor immune effectors damage gut lining

Epithelial loss

Mucosal injury and ulceration

Barrier damage

Ulcerated intestinal mucosa

Clinical result

Bloody diarrhea

The lesion-to-symptom chain is intestinal mucosal ulceration → bloody diarrhea.

Slide 39 · Acute GVHD: Morphology–manifestation coupling

Organ

Histologic / structural target

Expected clinical clue

Skin

Epidermal keratinocytes

Spreading rash

Liver

Small intrahepatic bile ducts

Jaundice

Intestine

Mucosal epithelium

Bloody diarrhea

Three organs can be explained by one donor T-cell–mediated pathogenic model.

Slide 40 · Application: Early multisystem syndrome

ILLUSTRATIVE TEACHING SCENARIO

An immunocompromised recipient develops a rash affecting the palms, jaundice and bloody diarrhea in the weeks following an allogeneic HSC transplant.

Clinicopathologic reasoning

The temporal setting and triad are compatible with acute GVHD.

Skin keratinocytes, small bile ducts and intestinal mucosa are the target structures.

This is an illustrative teaching scenario, not a real patient.

Slide 41 · Chronic GVHD: Not simply persistent acute rash

Chronic GVHD may follow an acute episode or begin insidiously.

A hallmark is extensive cutaneous injury with fibrosis and appendage loss.

The liver, gastrointestinal tract and immune system may also be injured.

Tissue sclerosis and multisystem dysfunction become dominant teaching features.

Slide 42 · Chronic skin GVHD: Dermal sclerosis

Epidermis

Dermis

Thinned epidermis

Thickened collagen (sclerosis)

SCHEMATIC (not a histologic specimen)

The dermis develops thickened collagen bundles.

This fibrotic pattern can resemble systemic sclerosis.

Original native PowerPoint schematic; Not genuine histopathology.

Slide 43 · Chronic skin GVHD: Epidermal atrophy

Epidermis

Dermis

Thinned epidermis

Thickened collagen (sclerosis)

SCHEMATIC (not a histologic specimen)

The epidermis becomes thinned because of atrophy.

Sparse interface inflammation and occasional injured keratinocytes may remain.

Based on the textbook description of Fig. 6.36C.

Slide 44 · Loss of cutaneous appendages in chronic GVHD

Destruction of skin appendages during chronic injury.

Appendage loss accompanies prominent dermal fibrosis.

These alterations reflect structural damage rather than a simple exanthem.

Observe the deep structural consequences of ongoing tissue injury.

Slide 45 · Acute versus chronic skin GVHD

Acute skin pattern

Interface inflammation and basal vacuolization.

Apoptotic or dyskeratotic keratinocytes.

Clinically prominent rash.

Chronic skin pattern

Thin, atrophic epidermis.

Thick dermal collagen with sclerosis.

Destruction of skin appendages.

Both may show sparse lymphocytes; The structural pattern differentiates them.

Slide 46 · Chronic hepatic GVHD: Cholestatic disease

Immune-mediated injury

Liver involvement during chronic GVHD

Persistent dysfunction

Chronic cholestatic liver disease

Clinical expression

Cholestatic jaundice

The source does not supply a biochemical cutoff or a histologic grading system.

Slide 47 · Chronic gastrointestinal GVHD: Stricture

Chronic injury

Sustained GI tract involvement

Structural damage

Esophageal narrowing / stricture

Functional impact

Impaired passage through the esophagus

Esophageal strictures among chronic manifestations.

Slide 48 · Chronic GVHD damages immune architecture

Thymus

Involution of the thymus

Lymph nodes

Depletion of lymphocytes

Defective host defense

Reduced immune competence

Clinical result

Recurrent infections

Immune-organ damage connects chronic GVHD to late susceptibility to infection.

Slide 49 · Recurrent infection in chronic GVHD

The thymus may involute, compromising the immune organ framework.

Lymphocyte depletion occurs in lymph nodes.

These abnormalities are associated with recurrent infections.

Immune deficiency may be a feature of GVHD as well as transplantation itself.

Slide 50 · Autoimmunity in chronic GVHD: Proposed mechanism

Grafted CD4+ cells

Donor helper T lymphocytes

Host B cells

Interact with recipient B lymphocytes

B-cell stimulation

Activation of autoantibody-capable clones

Autoantibodies

May contribute to autoimmune manifestations

This is presented by Robbins as a postulated mechanism, not an established universal pathway.

Slide 51 · Chronic GVHD can resemble autoimmune disease

Cutaneous sclerosis may resemble systemic sclerosis.

Other recipients develop manifestations interpreted as autoimmunity.

The source proposes donor CD4+ T-cell stimulation of host B cells as one explanation.

Clinical resemblance is not evidence of identical pathogenesis.

Slide 52 · Acute and chronic GVHD: Full clinicopathologic comparison

Domain

Acute form

Chronic form

Onset

Days to weeks

After acute disease or insidious

Skin

Rash; keratinocyte apoptosis

Atrophy; sclerosis; appendage loss

Liver

Small bile duct destruction; jaundice

Chronic cholestatic liver disease

GI tract

Mucosal ulceration; bloody diarrhea

Esophageal stricture

Immune effects

Donor-cell epithelial injury

Immune-organ depletion; autoimmunity

Categories here follow the Robbins 11th-edition source, not contemporary staging criteria.

Slide 53 · Application: Sclerosing skin disease

ILLUSTRATIVE TEACHING SCENARIO

After hematopoietic stem cell transplantation, a recipient develops tight skin. An illustrative skin section shows epidermal atrophy and thick dermal collagen bundles.

Clinicopathologic reasoning

The source pattern supports chronic cutaneous GVHD.

Epidermal thinning and dermal sclerosis contrast with acute keratinocyte apoptosis.

This scenario is constructed from textbook-described findings.

Slide 54 · Donor T-cell depletion: Direct protective effect

T lymphocytes in the donor graft are the key mediators of GVHD.

Removing donor T cells before infusion markedly reduces GVHD.

The approach as virtually eliminating this complication.

A mechanistically targeted intervention has consequences beyond preventing GVHD.

Slide 55 · The cost of donor T-cell depletion

Reduce donor T cells

Less T-cell–mediated GVHD

Lose protective functions

Support for graft and immune surveillance weakens

New problems

More graft failure, tumor recurrence and EBV-related lymphoma

The excerpt emphasizes this as a therapeutic trade-off rather than a simple win.

Slide 56 · Why donor T cells also support the graft

The textbook associates donor T lymphocytes with successful engraftment.

A proposed contribution is production of colony-stimulating factors (CSFs).

T-cell depletion may therefore raise the incidence of graft failure.

CSF production is suggested, not demonstrated as the only mechanism.

Slide 57 · The graft-versus-leukemia contribution

Donor immune cells can participate in control of recipient leukemia cells.

Removing these donor T cells increases leukemic tumor recurrence in the source.

GVHD reduction must be weighed against loss of antitumor immune control.

The same donor-cell alloreactivity can cause harm and confer antileukemic benefit.

Slide 58 · Control of EBV-infected B-cell clones

Donor T cells help suppress Epstein–Barr virus–infected B-cell clones.

Extensive T-cell depletion can undermine this immune surveillance.

An increased incidence of EBV-related B-cell lymphoma is described.

Post-transplant lymphoid cancer risk depends in part on immune control.

Slide 59 · Donor T cells: Harmful and protective roles

Immune function

Benefit or harm

Effect of depletion described

Alloreactivity to host

GVHD tissue injury

Less GVHD

Support of HSC engraftment

Graft persistence

More graft failure

Leukemia-cell control

Antitumor effect

More recurrence

EBV-infected B-cell control

Immune surveillance

More EBV-related B-cell lymphoma

These are associations; No event rates are specified.

Slide 60 · Application: The T-cell depletion dilemma

ILLUSTRATIVE TEACHING SCENARIO

A transplant team considers depleting donor T lymphocytes to lessen GVHD after allogeneic HSC transplantation.

Clinicopathologic reasoning

Expected benefit: Marked reduction in GVHD.

Recognized costs: Graft failure, leukemia recurrence and EBV-related B-cell lymphoma.

The teaching issue is balancing tissue injury against immune protection.

Slide 61 · Immunodeficiency after HSC transplantation

Profound immune suppression is a frequent post-transplant complication.

It reflects accumulated effects of past treatment, conditioning and delayed immune recovery.

Transferred lymphocytes may also attack host immune cells.

Infection risk has multiple causal routes, not a single mechanism.

Slide 62 · Four contributors to post-transplant immune deficiency

Previous therapy

Leukemia treatment or other preceding therapy

Conditioning

Myeloablation and lymphodepletion

Delayed rebuilding

Slow repopulation of the immune system

Graft-mediated injury

Host immune cells attacked by donor lymphocytes

This causal map reproduces the four factors enumerated in the supplied text.

Slide 63 · Prior therapy and pretransplant immune injury

Underlying-disease treatment may already compromise host immunity.

Myeloablation and lymphodepletion add further cell loss.

Thus immune deficits can predate successful donor-cell engraftment.

The timeline of immune suppression starts before the graft is infused.

Slide 64 · Immune reconstitution is not immediate

Following transplantation, immune-system repopulation takes time.

Delayed replacement leaves a period of profound immunodeficiency.

This vulnerability can persist despite establishment of transplanted cells.

Do not equate engraftment with immediate fully effective host defense.

Slide 65 · CMV infection: A major post-HSC-transplant threat

Latent virus

Cytomegalovirus remains in the host

Immune suppression

Antiviral immune control is impaired

Reactivation

Latent CMV becomes active

Organ disease

CMV-associated pneumonitis may be fatal

Reactivation of latent CMV as a particularly important infection.

Slide 66 · CMV pneumonitis: Clinicopathologic importance

CMV reactivation is emphasized among infections after HSC transplantation.

Pneumonitis is a potentially fatal complication.

This complication illustrates the clinical cost of impaired antiviral immunity.

The supplied section provides no incidence, diagnostic assay or treatment regimen.

Slide 67 · Two immune complications, two different mechanisms

GVHD

Donor immune effectors attack host tissues.

Produces skin, hepatic, intestinal and chronic systemic injury.

Immunodeficiency

Host defenses fail to protect against microorganisms.

Predisposes to opportunistic infection and viral reactivation.

The processes are related and may coexist, but should not be conflated.

Slide 68 · Application: Serious pulmonary infection

ILLUSTRATIVE TEACHING SCENARIO

An HSC-transplant recipient remains markedly immunocompromised and develops pneumonitis. The clinical discussion identifies activation of latent cytomegalovirus.

Clinicopathologic reasoning

CMV reactivation is an important post-transplant mechanism.

Myeloablation, slow immune reconstitution and other factors impair antiviral defense.

The source warns that CMV pneumonitis can be fatal.

Slide 69 · Integrated view: Benefit, alloreactivity and vulnerability

Therapeutic objective

Repopulate marrow with functioning HSCs

Engraftment

Conditioning opens niches

Immune conflict

Donor T cells may injure host tissue

Immune deficit

Suppression creates infectious vulnerability

Understanding transplantation requires both hematopoietic recovery and immune biology.

Slide 70 · Rapid recognition: Complication → mechanism

Finding

Likely process

Textbook explanation

Early rash + bloody diarrhea

Acute GVHD

Epithelial injury in skin and gut

Sclerosis + epidermal atrophy

Chronic GVHD

Fibrosing injury of skin

Recurrent infections + lymphoid depletion

Chronic GVHD immune effects

Thymic and nodal injury

CMV pneumonitis

Post-transplant immunodeficiency

Loss of control over latent infection

A pattern-recognition table, not a validated diagnostic algorithm.

Slide 71 · Essential conclusions

Conditioning creates marrow niches for donor HSC engraftment but depletes host immune cells.

Donor T-cell recognition of host HLA drives GVHD; epithelial apoptosis and later sclerosis explain manifestations.

T-cell depletion suppresses GVHD but can impair engraftment, leukemia control and EBV surveillance.

Delayed immune reconstitution contributes to infection risk, notably CMV reactivation.

Connect each complication to the cells and tissue structures that produce it.