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Causes of Blindness
1) Cataract
2) Injuries
3) Diabetic Retinopathy
4) Glaucoma
5) Refractive errors
6) Hereditary diseases of eye
7) ARMD
8) Corneal blindness
Human Resources
1) Total Ophthalmologists in India (approximately) :
a) Registered : 26,700
b) Unregistered : 12,000
2) New addition of Ophthalmologists every year: 1,500
3) Total No. of eye banks : 764 (In India)
4) Viable eye banks : 420
Corneal blindness is one of the leading causes of blindness
in the world.
World Health Organization (WHO) reports estimate that
approximately 5% of the world’s population is blind due to
corneal diseases alone.
In India, approximately 68 lakh people suffer from corneal
blindness in at least one eye; of these, 11 lakh people are
blind in both their eyes.
On an average 40-50 percent donated eyes/corneas are
utilized for corneal transplantation annually.
More than 1,00,000 corneal transplants are required
annually in India.
25 to 30 thousand eyes are collected every year.
Current annual transplant number is 25,000.
around 11 lakh people are suffering from corneal blindness
in India and 30,000 new cases are being added each year,
whereas, only 25,000 corneal transplants are conducted
every year in India.
Important Corneal Blindness causes
1) Corneal opacities
2) Corneal dystrophies
3) Corneal injuries
4) Vitamin A deficiency
5) ABK, PBK, BSK
6) Congenital corneal blindness
Definition of Corneal Graft Rejection
1) Graft rejection is an active phenomena, where in there
will be immunological reaction from host antigens
against donor corneal tissue and the grafted cornea
should be clear for at least 10 to 15 days after
transplantation. This graft rejection is different from
graft failure.
Graft Rejection v/s Graft Failure
What is the difference…?
If there is corneal graft rejection, it may lead to graft failure
or it may (cornea) turn back to normal clear cornea with
timely prompt and timely treatment.
If the graft is failed, it is failed forever.
Primary Graft failure
Primary donor graft failure is defined as cornea edema
that never clears from the immediate postoperative
period secondary to inherent deficiencies in the donor
graft, surgical trauma, or improperly stored tissue.
History of organ transplantation:
Examples in mythology
Lord Ganesha’s head replaced with Elephant head
Bhakhta kanappa (eye donation/transplant)
• Autograft -within same individual
•Isograft --- From genetically identical twins
•Allograft- From genetically different
member of the same species.
•Xenograft- From different species
•Future grafts-transgenic species
TYPES OF GRAFTS:
• Heart
• Lung
• Kidney
• Liver
• Skin
• Blood & components
• Pancreas
• Bone
• Tendon
• Muscle
• Cornea
• Intestine
Human organs that can be transplanted:
Human organ transplant Act
HOTA Act (1994) & its amendments:
• Ethical aspects
• Social aspects
• Financial aspects
• Humanitarian aspects
Jeevandan Program, Government of Andhra Pradesh
•The Transplantation of Human Organs Act, 1994 was
enacted by the Parliament during 1994 and came into
force on February 4, 1995 in the States of Goa, Himachal
Pradesh and Maharashtra and all the Union Territories.
Thereafter it was adopted by all States except the States of
Jammu & Kashmir and Andhra Pradesh, which have their
own legislations to regulate transplantation of Human
Organs
Types of Keratoplasty:
• Full thickness Penetrating Keratoplasty
• Lamellar Keratoplasty
• Grafting of Superficial layers (including stroma)
• Endothelial Graft(s)
• DALK(Deep anterior Lamellar Keratoplasty)
• DSEK(Descemet Stripping Endothelial Keratoplasty)
• DMEK(Descemet Membrane Endothelial Keratoplasty)
History of evolution of
corneal surgeries
History of corneal surgeries
• Galen 130–200 Idea of restoring transparency of an opaque cornea.
• Darwin in 1760 idea of removal of opaque cornea by trephination.
• Bigger 1837 First successful transplant in animals.
• Von Hippel 1886 First lamellar transplant in 30 patients.
• Zirm1905 Penetrating transplant with permanent success
• Filatov1935 First eye bank (Odessa, Russia)
• Paton1945 First US eye bank (New York).
• Maumanee1941 Graft rejection recognized as a clinical en
• 1961Eye Bank Association of America.
• 1974McCarey-Kaufmann donor preservation.
• 1989First idea of use of laser for trephination. Jones1998 Endothelial
lamellar keratoplasty
• Terry2001 Deep lamellar endothelial keratoplasty
• Anwar2002 Big-bubble technique of DAL.
• Price2005 Descemet’s stripping endothelial keratoplasty
.
Classification of corneal Graft Rejection:
Epithelial
Chronic Stromal
Hyperacute stromal
Chronic Focal/ Endothelial
Combined stromal and
endothelial
Causes for corneal graft rejection:
• Donor Factors
• Host Factors
• Technical Factors
• Post operative infection(s)
Pre-operative causes
Per-operative causes
Post-operative causes
Pre-operative causes
1) Donor factors
a) Antigen load of donor
b) HLA / ABO incompatibility
c) Duration of tissues storage
d) Technique of corneal button cutting
e) Vaccination of Flu, Covid-19
Pre-operative causes
2) Host corneal factors
a) Vascularization
b) Failed graft and regraft
c) Ocular surface disease like Dry eye, chemical
injury, Lime injury, SJ syndrome, Pemphigoid,
facial palsy, surface infection, viral keratitis
d) ABO incompatibility
e) Post excimer laser
Pre-operative causes
2) Host corneal factors
f) Pilocarpine and other drugs
g) PAS
h) Un controlled glaucoma
i) Young aged recipient
j) Large graft
k) Interstitial keratitis
Per-operative causes
1) Large graft
2) Eccentric graft
3) PAS
4) Bilateral graft
5) Loose sutures
6) Previous anterior segment surgeries
Post-operative causes
1) Loose sutures
2) Exposed suture edges
3) Blepharitis
4) Entropion
5) Trichiasis
6) PAS
7) Posterior Synechiae
8) Vascularization
Symptoms of Graft Rejection
• Redness
• Pain
• Photophobia
• Diminution of vision
Signs of Graft Rejection
• Conjunctival Congestion
• Circumciliary Congestion
• Chemosis
• Corneal Edema
• Raised IOP
• Keratic precipitates
• Sub-Epithelial infiltrates
• Stromal infiltrates &
vascularization
• Endothelial Rejection Line
• Khodadoust Line
• Anterior Chamber Flare &
Cells
Immuno-Pathology Of Corneal Graft Rejection
Corneal Immune privilege systems:
1. Avascularity
2. Lack of lymphatics
3. ACAID (anterior chamber associated immune
deviations)
Despite of all the above-mentioned privileges, graft
rejection still occurs but at lower rates when compared to
other organ transplants, because of mismatching of
Donor to Recipient MHC/HLA antigens and rarely ABO
incompatibility can be another cause for graft rejection.
MECHANISM OF CORNEAL GRAFT FAILURE
•Type IV cell-mediated immune reaction.
•Role of CD-4 cells:
•Foreign MHC class II antigens act as a strong stimulus
and can be recognized by host CD4+ T cells. The host
Langerhans cells can also process foreign class I
antigen and present it in conjunction with self-class Il
molecules to host CD4 T cells. The result of either
mechanism is CD4 T-cell activation
Activated CD4 T cells release IL-2 and other lymphokines that
stimulate the proliferation and activation of CD4 T cells, cytotoxic T
cells, and B lymphocytes.
• Role of CD-8 cells: Host cytotoxic T cells (CD8+) can recognize foreign
class I cell-surface antigens on the surface of donor cells. They result
in lysis of the donor cells. NK activity also has a cytotoxic role.
• B Lymphocytes
• Antibody production by B cells enables opsonization, complement
binding, and facilitation antibody-dependent cell-mediated
cytotoxicity (K cell activity). Exaggerated response by induction of
donor MHC class II
Differential Diagnosis of Corneal Graft Rejection
1) Disciform viral keratitis
2) Infectious endophthalmitis
3) Endotheliitis
4) Epithelial down growth
5) Large graft failure
6) Posner Schlossman syndrome
Differential Diagnosis:
LATE GRAFT FAILURE:
•Gradual onset of
graft edema
•No inflammation or
KPs
STERILE/INFECTIOUS
ENDOPHTHALMITIS
•Severe ocular
inflammation
•Hypopyon
•Vitreous infiltrates
Differential Diagnosis:
EPITHELIAL DOWNGROWTH
RECURRENT HERPETIC
KERATITIS
• H/o graft in herpetic cornea
• No endothelial line in
presence of intense AC
reaction
• Response to topical Antiviral
therapy
• Clumps of cell like material in
AC
• No response to CS
• Associated raised IOP
unresponsive to medical
therapy
Management of Corneal Graft Rejection
1) Local and systemic steroids
 Prednisolone eye drops
 Dexamethasone eye drops
 Tablet – Prednisolone / wysolone
 IVMP pulse therapy – Dose for 3-5 days
2) Cytotoxic agents
 Azathioprine : 1 to 2mg per KG weight
 Cyclosporin ‘A’ – Topical / Systemic 0.50%
3) Combination of cytotoxic agents and steroids
Management of Corneal Graft Rejection
Newer Advances
4) Newer immune modulators
 Tacrolimus – FK-506 0.6mg / KG weight
5) Repamycin
 Lipophylic drug with high potency
6) Deoxy spergualin (DSG)
Management of Corneal Graft Rejection
Newer Advances
7) Tissue cultured corneal epithelial and
endothelial cells
8) Anti VEGF agents
9) Selective glucocorticoid receptor agonist (SEGRA)
Management of corneal graft rejection
Newer Advances:
• Cord Blood Stem cell culture for human
organ/tissue
• Cryo banking
• Bionic organs
Prevention of Corneal Graft Rejection
1) Proper case selection
2) Look for pre-operative risk factors
3) Patient education
4) Paramedical staff education
5) Prompt follow-up of patients
6) Treatment compliance – patient
Topical CS
• Pre op instillation in high
risk graft
• To be complimented with
systemic steroid therapy in
form of pulse steroid
dosage.
• Systemic steroids are to
be continued orally after
the initial pulse therapy.
Systemic CS
• Oral CS is recommended
in a higher doses than the
routine 60-80 mg daily
• It is to be tapered off
when the graft begins to
recover and usually cured
by 6-8 weeks
IV Pulse CS
• 500 mg in 150ml IV fluid
• The dose is to be repeated
after 48 hours.
• Oral maintenance to be
continued
Studies related to Corneal Graft Rejection
1) Australian Corneal transplant Registry
2) Singapore Corneal transplant Registry
3) UK Corneal Corneal transplant Registry
4) Corneal transplant collaborative research study
group
5) Corneal graft rejection treatment and follow up
group
CONCLUSIONS
CONCLUSIONS
1) Recent invention of component, layer by layer corneal
lamellar Keratoplasties has revolutionized the success
rate of cornea transplantation. With corneal
component layer by layer surgery. CGR rate has come
down to 0.56%
CONCLUSIONS
2) UV light treatment of cornea before grafting has
reduced post-operative vascularization
3) Trails are going on with corneal epithelial and
endothelial cell transplantation which were cultured
out side (invitro), just at the starting of CGR
4) Pre and Post operative measurement of corneal
thickness (pachymetry) is useful for knowing the
prognosis of graft success
CONCLUSIONS
6) Recent treatment trails with tacrolimus, cyclosporin ‘A’
along with corticosteroids is found to be more
effective treatment for CGR
7) Cytotoxic agents like methotrexate and
Cyclophosphamide are also tried for the treatment of
CGR
8) Drugs like Rapamycin, DSG (Deoxy Sergualin),
Mycophenolate, SEGRA (Selective Gluco Corticoid
Receptor Agonist) are still under experimental stage.
CONCLUSIONS
9) Anti VEGF drugs like Bevacizumab has been tried to
prevent corneal vascularization at the starting of
corneal graft rejection
THANK YOU

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CGR PPT by DrPPS PRABHAKRA SASTRY-10-2023.pptx

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  • 3. Causes of Blindness 1) Cataract 2) Injuries 3) Diabetic Retinopathy 4) Glaucoma 5) Refractive errors 6) Hereditary diseases of eye 7) ARMD 8) Corneal blindness
  • 4. Human Resources 1) Total Ophthalmologists in India (approximately) : a) Registered : 26,700 b) Unregistered : 12,000 2) New addition of Ophthalmologists every year: 1,500 3) Total No. of eye banks : 764 (In India) 4) Viable eye banks : 420
  • 5. Corneal blindness is one of the leading causes of blindness in the world. World Health Organization (WHO) reports estimate that approximately 5% of the world’s population is blind due to corneal diseases alone.
  • 6. In India, approximately 68 lakh people suffer from corneal blindness in at least one eye; of these, 11 lakh people are blind in both their eyes. On an average 40-50 percent donated eyes/corneas are utilized for corneal transplantation annually.
  • 7. More than 1,00,000 corneal transplants are required annually in India. 25 to 30 thousand eyes are collected every year.
  • 8. Current annual transplant number is 25,000. around 11 lakh people are suffering from corneal blindness in India and 30,000 new cases are being added each year, whereas, only 25,000 corneal transplants are conducted every year in India.
  • 9. Important Corneal Blindness causes 1) Corneal opacities 2) Corneal dystrophies 3) Corneal injuries 4) Vitamin A deficiency 5) ABK, PBK, BSK 6) Congenital corneal blindness
  • 10. Definition of Corneal Graft Rejection 1) Graft rejection is an active phenomena, where in there will be immunological reaction from host antigens against donor corneal tissue and the grafted cornea should be clear for at least 10 to 15 days after transplantation. This graft rejection is different from graft failure.
  • 11. Graft Rejection v/s Graft Failure What is the difference…?
  • 12. If there is corneal graft rejection, it may lead to graft failure or it may (cornea) turn back to normal clear cornea with timely prompt and timely treatment. If the graft is failed, it is failed forever.
  • 13. Primary Graft failure Primary donor graft failure is defined as cornea edema that never clears from the immediate postoperative period secondary to inherent deficiencies in the donor graft, surgical trauma, or improperly stored tissue.
  • 14. History of organ transplantation: Examples in mythology Lord Ganesha’s head replaced with Elephant head Bhakhta kanappa (eye donation/transplant)
  • 15.
  • 16. • Autograft -within same individual •Isograft --- From genetically identical twins •Allograft- From genetically different member of the same species. •Xenograft- From different species •Future grafts-transgenic species TYPES OF GRAFTS:
  • 17. • Heart • Lung • Kidney • Liver • Skin • Blood & components • Pancreas • Bone • Tendon • Muscle • Cornea • Intestine Human organs that can be transplanted:
  • 19. HOTA Act (1994) & its amendments: • Ethical aspects • Social aspects • Financial aspects • Humanitarian aspects Jeevandan Program, Government of Andhra Pradesh
  • 20. •The Transplantation of Human Organs Act, 1994 was enacted by the Parliament during 1994 and came into force on February 4, 1995 in the States of Goa, Himachal Pradesh and Maharashtra and all the Union Territories. Thereafter it was adopted by all States except the States of Jammu & Kashmir and Andhra Pradesh, which have their own legislations to regulate transplantation of Human Organs
  • 21. Types of Keratoplasty: • Full thickness Penetrating Keratoplasty • Lamellar Keratoplasty • Grafting of Superficial layers (including stroma) • Endothelial Graft(s) • DALK(Deep anterior Lamellar Keratoplasty) • DSEK(Descemet Stripping Endothelial Keratoplasty) • DMEK(Descemet Membrane Endothelial Keratoplasty)
  • 22. History of evolution of corneal surgeries
  • 23. History of corneal surgeries • Galen 130–200 Idea of restoring transparency of an opaque cornea. • Darwin in 1760 idea of removal of opaque cornea by trephination. • Bigger 1837 First successful transplant in animals. • Von Hippel 1886 First lamellar transplant in 30 patients. • Zirm1905 Penetrating transplant with permanent success • Filatov1935 First eye bank (Odessa, Russia) • Paton1945 First US eye bank (New York).
  • 24. • Maumanee1941 Graft rejection recognized as a clinical en • 1961Eye Bank Association of America. • 1974McCarey-Kaufmann donor preservation. • 1989First idea of use of laser for trephination. Jones1998 Endothelial lamellar keratoplasty • Terry2001 Deep lamellar endothelial keratoplasty • Anwar2002 Big-bubble technique of DAL. • Price2005 Descemet’s stripping endothelial keratoplasty .
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  • 26. Classification of corneal Graft Rejection: Epithelial Chronic Stromal Hyperacute stromal Chronic Focal/ Endothelial Combined stromal and endothelial
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  • 43. Causes for corneal graft rejection: • Donor Factors • Host Factors • Technical Factors • Post operative infection(s)
  • 45. Pre-operative causes 1) Donor factors a) Antigen load of donor b) HLA / ABO incompatibility c) Duration of tissues storage d) Technique of corneal button cutting e) Vaccination of Flu, Covid-19
  • 46. Pre-operative causes 2) Host corneal factors a) Vascularization b) Failed graft and regraft c) Ocular surface disease like Dry eye, chemical injury, Lime injury, SJ syndrome, Pemphigoid, facial palsy, surface infection, viral keratitis d) ABO incompatibility e) Post excimer laser
  • 47. Pre-operative causes 2) Host corneal factors f) Pilocarpine and other drugs g) PAS h) Un controlled glaucoma i) Young aged recipient j) Large graft k) Interstitial keratitis
  • 48. Per-operative causes 1) Large graft 2) Eccentric graft 3) PAS 4) Bilateral graft 5) Loose sutures 6) Previous anterior segment surgeries
  • 49. Post-operative causes 1) Loose sutures 2) Exposed suture edges 3) Blepharitis 4) Entropion 5) Trichiasis 6) PAS 7) Posterior Synechiae 8) Vascularization
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  • 54. Symptoms of Graft Rejection • Redness • Pain • Photophobia • Diminution of vision
  • 55. Signs of Graft Rejection • Conjunctival Congestion • Circumciliary Congestion • Chemosis • Corneal Edema • Raised IOP • Keratic precipitates • Sub-Epithelial infiltrates • Stromal infiltrates & vascularization • Endothelial Rejection Line • Khodadoust Line • Anterior Chamber Flare & Cells
  • 56.
  • 57. Immuno-Pathology Of Corneal Graft Rejection Corneal Immune privilege systems: 1. Avascularity 2. Lack of lymphatics 3. ACAID (anterior chamber associated immune deviations)
  • 58. Despite of all the above-mentioned privileges, graft rejection still occurs but at lower rates when compared to other organ transplants, because of mismatching of Donor to Recipient MHC/HLA antigens and rarely ABO incompatibility can be another cause for graft rejection.
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  • 62. MECHANISM OF CORNEAL GRAFT FAILURE •Type IV cell-mediated immune reaction. •Role of CD-4 cells: •Foreign MHC class II antigens act as a strong stimulus and can be recognized by host CD4+ T cells. The host Langerhans cells can also process foreign class I antigen and present it in conjunction with self-class Il molecules to host CD4 T cells. The result of either mechanism is CD4 T-cell activation
  • 63. Activated CD4 T cells release IL-2 and other lymphokines that stimulate the proliferation and activation of CD4 T cells, cytotoxic T cells, and B lymphocytes. • Role of CD-8 cells: Host cytotoxic T cells (CD8+) can recognize foreign class I cell-surface antigens on the surface of donor cells. They result in lysis of the donor cells. NK activity also has a cytotoxic role. • B Lymphocytes • Antibody production by B cells enables opsonization, complement binding, and facilitation antibody-dependent cell-mediated cytotoxicity (K cell activity). Exaggerated response by induction of donor MHC class II
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  • 73. Differential Diagnosis of Corneal Graft Rejection 1) Disciform viral keratitis 2) Infectious endophthalmitis 3) Endotheliitis 4) Epithelial down growth 5) Large graft failure 6) Posner Schlossman syndrome
  • 74. Differential Diagnosis: LATE GRAFT FAILURE: •Gradual onset of graft edema •No inflammation or KPs STERILE/INFECTIOUS ENDOPHTHALMITIS •Severe ocular inflammation •Hypopyon •Vitreous infiltrates
  • 75. Differential Diagnosis: EPITHELIAL DOWNGROWTH RECURRENT HERPETIC KERATITIS • H/o graft in herpetic cornea • No endothelial line in presence of intense AC reaction • Response to topical Antiviral therapy • Clumps of cell like material in AC • No response to CS • Associated raised IOP unresponsive to medical therapy
  • 76. Management of Corneal Graft Rejection 1) Local and systemic steroids  Prednisolone eye drops  Dexamethasone eye drops  Tablet – Prednisolone / wysolone  IVMP pulse therapy – Dose for 3-5 days 2) Cytotoxic agents  Azathioprine : 1 to 2mg per KG weight  Cyclosporin ‘A’ – Topical / Systemic 0.50% 3) Combination of cytotoxic agents and steroids
  • 77. Management of Corneal Graft Rejection Newer Advances 4) Newer immune modulators  Tacrolimus – FK-506 0.6mg / KG weight 5) Repamycin  Lipophylic drug with high potency 6) Deoxy spergualin (DSG)
  • 78. Management of Corneal Graft Rejection Newer Advances 7) Tissue cultured corneal epithelial and endothelial cells 8) Anti VEGF agents 9) Selective glucocorticoid receptor agonist (SEGRA)
  • 79. Management of corneal graft rejection Newer Advances: • Cord Blood Stem cell culture for human organ/tissue • Cryo banking • Bionic organs
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  • 81. Prevention of Corneal Graft Rejection 1) Proper case selection 2) Look for pre-operative risk factors 3) Patient education 4) Paramedical staff education 5) Prompt follow-up of patients 6) Treatment compliance – patient
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  • 84. Topical CS • Pre op instillation in high risk graft • To be complimented with systemic steroid therapy in form of pulse steroid dosage. • Systemic steroids are to be continued orally after the initial pulse therapy. Systemic CS • Oral CS is recommended in a higher doses than the routine 60-80 mg daily • It is to be tapered off when the graft begins to recover and usually cured by 6-8 weeks IV Pulse CS • 500 mg in 150ml IV fluid • The dose is to be repeated after 48 hours. • Oral maintenance to be continued
  • 85. Studies related to Corneal Graft Rejection 1) Australian Corneal transplant Registry 2) Singapore Corneal transplant Registry 3) UK Corneal Corneal transplant Registry 4) Corneal transplant collaborative research study group 5) Corneal graft rejection treatment and follow up group
  • 87. CONCLUSIONS 1) Recent invention of component, layer by layer corneal lamellar Keratoplasties has revolutionized the success rate of cornea transplantation. With corneal component layer by layer surgery. CGR rate has come down to 0.56%
  • 88. CONCLUSIONS 2) UV light treatment of cornea before grafting has reduced post-operative vascularization 3) Trails are going on with corneal epithelial and endothelial cell transplantation which were cultured out side (invitro), just at the starting of CGR 4) Pre and Post operative measurement of corneal thickness (pachymetry) is useful for knowing the prognosis of graft success
  • 89. CONCLUSIONS 6) Recent treatment trails with tacrolimus, cyclosporin ‘A’ along with corticosteroids is found to be more effective treatment for CGR 7) Cytotoxic agents like methotrexate and Cyclophosphamide are also tried for the treatment of CGR 8) Drugs like Rapamycin, DSG (Deoxy Sergualin), Mycophenolate, SEGRA (Selective Gluco Corticoid Receptor Agonist) are still under experimental stage.
  • 90. CONCLUSIONS 9) Anti VEGF drugs like Bevacizumab has been tried to prevent corneal vascularization at the starting of corneal graft rejection

Editor's Notes

  1. Following transplant surgery, upregulation of pro-inflammatory cytokines, adhesion molecules and pro-angiogenic factors results in corneal infiltration of immune cells and formation of new blood and lymphatic vessels. (II). Antigen presenting cells (APCs), which acquire MHC class II egress from the cornea through lymphatic vessels to the draining lymph nodes, where they prime naïve T cells (Th0). (III). Primed T cells undergo clonal expansion and differentiate primarily into IFNγ-secreting CD4+ Th1 cells. (IV). These Th1 cells, migrate through blood vessels toward the graft, where they mount a delayed-type hypersensitivity response against the allogeneic tissue, resulting in graft opacification and failure.
  2. Treatment with topical corticosteroids for prevention in high-risk grafts consists of preoperative instillation of four times a day for 1 week. Postoperative instillation is given hourly for 3 days, every 2 hours for 15 days, four times daily for 2 months, three times daily for 2 months, twice daily for 3 months, and once daily for 4 more months. The treatment regimen in acute rejection consists of hourly instillation of topical steroids until the rejection process gets arrested or reversed. This is to be complimented with systemic steroid therapy in form of pulse steroid dosage. Systemic steroids are to be continued orally after the initial pulse therapy. Maintenance and tapering of systemic steroids will depend on the time of postoperative presentation of the rejection episode, severity of the graft rejection, and the response to the therapy