• Information
  1. Types of Transplants
  2. Graft Survival Rates 1993-2002 (Table 1)
  3. Tissue Typing
  4. Major Histocompatibility Complex
  5. ABO Complex
  6. Rejection
  7. Hyperacute Rejection
  8. Acute Rejection
  9. Chronic Rejection
  10. Immunosuppression
  11. Graft Versus Host Disease
  12. Infection Prevention in Organ Transplants
  13. Lymphoproliferative Disorders
  14. Malignant Skin Tumors
  15. Xenotransplantation

A. Types of Transplants

1. Autologous (mainly stem cells)
2. Syngeneic (twins)
3. Allogeneic (unrelated)
4. Xenogeneic (animal organ) [36]
5. Living versus Cadavaric
6. Rejection of transplant by donor is currently major problem
   1. The more closely related the donor and recipient are, the less likely rejection
   2. The ABO and HLA protein groups are the most important for "similarity"
   3. Immunosuppression is currently required to prevent rejection
   4. Immunosuppression increases risk of infection and malignancy

B. Graft Survival Rates 1993-2002 (Table 1, Ref [2])

1. Most readily accepted graft is one similar to self at HLA and ABO
2. HLA are human leukocyte antigens: human major histocompatibility complex (MHC) proteins
3. Blood type ABO compatibility usually required as well
4. HLA Class I MHC Proteins
   1. Class II MHC (HLA-D) are tightly linked to Class I human MHC, HLA-A and -B
   2. Therefore, class I MHC match usually implies HLA-D match
   3. Cadavaric kidney grafts do not require HLA-A or -B matching
   4. HLA-A,B,D matched kidneys show only ~10% improvement over HLA-D only matched

D. Major Histocompatibility Complex (MHC)

1. Chromosomal Locations are highly polymorphic
   1. Human chromosome (chr) 6 called the HLA complex
   2. HLA is human leukocyte antigen
   3. Mouse chr 17 contains the H2 system (analogous to human HLA system)
2. Human HLA Complex
   1. Contains over 200 genes
   2. >40 of these genes encode specific leukocyte proteins
   3. Four major types of genes in HLA complex
   4. Class I and II genes directly involved in lymphocyte-based immunity
   5. Class III genes: complement system members (Factor B), inflammatory genes (such as TNFa), heat shock proteins
3. Class I MHC Genes
   1. Consists of two chains: alpha polypeptide (chr 6) with ß2-microglobulin (chr 15)
   2. There are 20 Class I genes in HLA region
   3. The Class Ia genes, HLA-A, B and C, are classic genes involved in immunity
   4. Class Ia HLA are expressed on all somatic cells of the body
   5. Level of expression depends on tissue
   6. Interferon gamma and other stimuli can increase Class I gene expression
   7. Role of Class Ia proteins is to present antigens mainly to CD8+ cytotoxic T lymphocytes
   8. Role of Class Ib proteins is variable; includes HLA-E, F, G, HFE, MICA and B, TAP genes
4. Class II MHC Genes
   1. Consists of two chains: alpha and beta both coded on chr 6
   2. There are five families of immune-related Class II (HLA-D) genes
   3. These families are designated HLA-DM, O, P, Q, and R (DP, Q and R are most important)
   4. The families are followed by A or B to designate alpha or beta chain
   5. Finally, specific polymorphisms (alleles) of HLA-D genes are designated by asterisk and allele number
   6. Thus, HLA-DRB1*0401 means Class II (D locus), R family, ß1 chain, allele number 0401
   7. Class II genes are expressed only on "professional" antigen presenting cells including B cells, macrophages, dendritic cells, activated T cells, and thymic epithelial cells
5. Role of MHC in Transplantation Success [46]
   1. MHC believed to have major role in transplantation success
   2. Pre-existing anti-MHC panel reactive antibodies (PRA) associated with rejection
   3. 10-year graft survival rates in >4000 kidney transplants from HLA-indentical siblings:
   4. Graft survival with no PRA 72%
   5. Graft survival with 1-50% PRA 63%
   6. Graft survival with >50% PRA 55%
   7. Therefore, non-HLA mechanisms are involved in long term graft function

E. ABO Complex

1. ABO blood group antigens critical since these Ags are usually expressed on endothelium
2. ABO compatibility essential for vascularized tissue allografts including kidney and heart
3. Not appear to be required for Bone Marrow Transplant (BMT)
4. ABO compatibility not required in infants (heart transplants) because anti-ABO antibodies have not yet formed [35]

F. Rejection [2,3,21]

1. Classified into hyperacute, acute, and chronic
2. Hyperacute: minutes to hours after transplant
   1. Due to preformed Abs to donor tissue antigens
   2. Most commonly observed in xenograft transplantation [36]
3. Acute: lymphocytic anti-graft response
4. Chronic: mainly a vasculitis, with graft endothelial damage by host lymphocytes
5. Goal of Current Transplantation Medicine
   1. Permit engraftment without severe immunosuppression to the host
   2. This is called tolerance, and mechanisms for inducing tolerance are being studied [37]

G. Hyperacute Rejection

1. Uncommon at this time, due to pre-transplant screening for host anti-graft antibodies
2. Abs and C3b fragment seen in transplant vasculature very soon after transplant
3. Graft vascular clotting occurs leading to ischemia; eventual necrosis and death
4. Renal Hyperacute Rejection
   1. Normal transplanted kidney is brown-red color
   2. Hyperacute rejected kidney is dark blue
   3. Rejected graph has glomerular and pan-vascular thrombosis, vasculitis
5. Immunoadsorption of anti-HLA Abs prior to grafting may reduce hyperacute rejection
6. In xenotransplantation, hyperacute rejection is main problem [36]
   1. This is due to presence of alpha-galactosyl groups on surfaces of most animal cells
   2. Humans have relatively high levels of anti-alpha-galactosyl Abs
   3. Baboons and chimpanzees, like humans, have no alpha-galactosyl residues
   4. Gene manipulation and

H. Acute Rejection [3,13]

1. Pathogenesis
   1. Host (H) lymphocytes exposed to shed and fixed graft (G) alloantigen
   2. Host Lymphocyctes proliferate in the draining lymph nodes
   3. Antigen specific cells accumulate in graft; some recruitment of nonspecific host cells
   4. Target injured by host CTL, innocent bystander reactions, or vascular thrombosis
2. T Lymphocyte Activation [37]
   1. Both CD4+ helper and CD8+ cytotoxic T lymphocytes are involved
   2. Antigen is presented by donor and host dendritic cells and macrophages
   3. Accessory T cell activation signals are involved (such as CD28, CD40L, CD2)
   4. Activated T cells express IL-2R and CD40L (CD154), as well as other molecules
   5. Initial T cell activation leads to production of Interleukin 2 (IL-2) and other cytokines
   6. IL-2 binds to IL-2 receptors (IL-2R) and fully activates T lymphocytes [16]
   7. Current research is focusing on blocking accessory signals to prevent/reduce rejection
3. Other Cell Types [22,37]
   1. CD4+ T cells help recruit other effector cells to graft by producing cytokines
   2. Cytokines induce leukocyte adhesion molecule expression
   3. LAMs allow leukocyte binding to endothelium and enter grafted tissue
   4. Expression of ß2- (CD11/18) and ß1-integrins (VLA-4) occur in activated leukocytes
   5. These bind ICAM-1 and VCAM-1 on endothelium
   6. Neutrophils, eosinophils and monocytes/macrophages are recruited to graft site
   7. Macrophages express CD40, CD80/86, and other costimulatory molecules
   8. B cells also recruited to graft area and stimulate T cells, may produce antibodies
4. Damaged host tissue release bioactive tissue components [1]
   1. Clotting Factor III (Tissue Factor) and XII (Hagemann Factor)
   2. Damaged, activated endothelium (vasculitis)
   3. Activated endothelium expresses CD40 which can stimulate CD4+ T cells
   4. Stimulated CD4+ T cells produce increased inflammatory cytokines
   5. These play a role in chronic rejection, transplant atherosclerosis
5. Microarray gene expression profiling of renal allograft biopsies shows that histologically similar graft rejection is quite heterogeneous at the gene expression level [43]

I. Chronic Rejection [2,3,21]

1. Particularly a problem with renal allografts
2. Occurs months to years post-transplant leading to gradual graft deterioration
3. Major finding is vascular occlusions in graft, thickened intima, atherosclerotic changes
4. Thus, chronic rejection is mainly due to progressive obliteration of graft vasculature
5. Chronic graft rejection resembles a slow vasculitic process
6. Maternal HLA presence in sibling donor renal graft and not recipient is a better long term prognostic feature than the presence of paternal HLA on donor and not recipient [19]

J. Immunosuppression [3,10,21]

1. Classification of Immunosuppressive Drugs (Table 1, Ref [3])
   1. Glucocorticoids
   2. Immunophilin binding drugs
   3. Cyclophilin binding calcineurin inhibitor: cyclosporin (CsA)
      1. FKBP12-binding calcineurin inhibitor: tacrolimus
      2. Target of rapamycin inhibitors: sirolimus, everolimus
   4. Inhibitors of nucleotide synthesis
   5. Purine synthesis (IMPDH) inhibitor: mycophenolate
      1. Pyrimidine synthesis (DHODH) inhibitor: leflunomide (approved for rheumatoid arthritis)
   6. Antimetabolite: azathioprine
   7. Depleting Antibodies (Ab)
   8. Polyclonal antibodies: rabbit or horse antithymocyte globulin
      1. Mouse monoclonal (mAb) anti-CD3 Ab: muromonab-CD3
      2. Humanized mAb anti-CD52: alemtuzumab (Campath®; approved for leukemia)
      3. B-cell depleting mAb anti-CD20: rituxumab (Rituxan®; approved for lymphoma)
   9. Nondepleting Ab and Fusion Proteins
   10. Humanized anti-IL2 Receptor mAb anti-CD25: daclizumab, basiliximab
       1. Fusion protein CTLA4-Ig (LEA29Y, Belatacept): blocks costimulation
2. CsA (Sandimmune®)
   1. A fungal cyclic undecapeptide, binds to cyclophilin, a peptide-prolyl isomerase enzyme
   2. Cyclosporin-cyclophylin complexes bind calcineurin, inhibit its phosphatase activity
   3. This agent has revolutionized transplantation
   4. Substantial nephrotoxicity, can progress to renal failure [4]
   5. Neurotoxicities - primarily peripheral neuropathy
   6. Increased lymphoma and skin cancer incidence
   7. Use of low dose CsA (trough levels 75-125ng/mL) reduces incidence of neoplasms [9]
   8. Grapefruit juice inhibits CYP3A4 and should be avoided with CsA, sirolimus, tacrolimus [14]
3. Tacrolimus (FK-506; Prograf®)
   1. Binds to a peptide prolyl isomerase/phosphatase, not cyclophilin
   2. Specifically, binds to cytosolic proteins FKBP-12 and FKBP-25
   3. May have slightly greater efficacy in CsA "resistant" rejection episodes
   4. Synergistic combination with sirolimus
   5. Often used in liver transplantation
   6. Also effective in combination in islet cell transplants [29]
   7. Used in hand transplantation with basiliximab, permitted >1 year survival [30]
   8. After induction with anti-thymocyte globulin, tacrolimus monotherapy maintenance could often be weaned slowly to alternating days or 1-2 doses per week [42]
   9. Slow but steady weaning of tacrolimus should be considered during maintenance phase
4. Sirolimus (rapamycin, Rapamune®) [26,27]
   1. Approved by FDA for prevention of acute renal graft rejection with CsA
   2. Structurally related to tacrolimus, but blocks a distinct regulatory kinase
   3. This kinase is required for signalling through CD28 pathway
   4. Thus, rapamycin prevents T cell activation by blocking second signal
   5. Substantially reduced nephrotoxicity compared with CsA and Tacrolimus
   6. Used in combination with CsA, permits CsA dose reduction
   7. Combined with rabbit antithymocyte globulin induction, can be chronic as monotherapy [41]
   8. Superior to azathioprine as add on therapy with CsA
   9. Main side effects are thrombocytopenia, leukopenia, and hyperlipidemia
   10. Arthralgias and rash commonly occur
   11. Dose is 6mg loading and 2mg/d 4 hours after CsA is taken
   12. Dose as monotherapy in renal transplant is 15mg initially, then 5mg qd with modulated trough levels of 10-15µg/L [41]
5. OKT3 (Muromonab®) [25]
   1. Mouse anti-CD3 MAb binds to human CD3 part of T cell receptor on all T lymphocytes
   2. Not specific for resting or activated T cells
   3. Causes initial activation, then death, of T cells
   4. T cell activation leads to cytokine release and to "cytokine release syndrome"
   5. This syndrome includes arthralgias, myalgias, fevers, chills, hypoxia, nausea, vomiting
   6. Severe cytokine release syndrome can cause pulmonary edema and suffocation
   7. Cytokine release syndrome is reduced (not eliminated) by predmedication
   8. Anti-H1 and H2 histamine blockers, glucocorticoids, and acetaminophen are used
   9. OKT3 dose is 2.5-5mg iv, and is determined by peripheral CD3+ T cell count
   10. Agent is highly effective for prevention of acute rejection, particularly in high risk
   11. Anti-CD3 (hOKT3g1 - Ala-Ala) mitigates deterioration of insulin production during first year in new onset DM1 patients []
   12. Anti-IL2R blocking Abs appear to be as effective and are far better tolerated
6. Daclizumab (Zenapax®) [8,16,25]
   1. This is a humanized (IgG1 Fc) anti-IL2R alpha chain (CD25) Ab
   2. Reduces acute rejection episodes in moderate and high risk patients
   3. Reduced biopsy proven acute rejection from 35% to 22% in combination with other drugs
   4. Used in combination with CsA, glucocorticoids, and azathioprine or mycophenolate
   5. Reduced acute cellular rejection but increased death in cardiac transplant when used with CsA, glucocorticoids and mycophenolate [47]
   6. Good side effect profile with no increase in infections versus control in most studies
   7. Approved by FDA for prevention of acute renal allograft rejection
   8. Half life of the drug is ~20 days
   9. Dose is 1mg/kg over 15 minutes, given 24 hours before transplant and biweekly x 4
   10. May be used to reduce or eliminate need for glucocorticoids in islet cell transplants [29]
   11. Also active for treatment of pure red blood cell aplasia [49]
7. Basiliximab (Simulect®) [16,25]
   1. Chimeric IgG1 mouse Fab / human Fc monoclonal antibody
   2. Binds to anti-IL2R alpha chain (CD25) similar to daclizumab
   3. Used in combination with CsA, glucocorticoids and azathioprine
   4. Reduced acute rejection rate at 6 months from 44% to 30%
   5. Excellent side effect profile
   6. Approved by FDA for prevention of acute renal allograft rejection
   7. Half-life of the drug is ~7 days
   8. Dose is 20mg IV on day of transplantation and 20mg IV four days later
8. Mycophenolate mofetil (CellCept®)
   1. Adjunctive therapy to CsA + glucocorticoids
   2. Impairs de novo purine synthesis - reduces B cell proliferation and antibody production
   3. Approved for reduction of acute rejection episodes in renal allograft transplants
   4. Better tolerated than azathioprine (no laboratory monitoring required)
   5. Efficacy similar to azathioprine with higher cost for preventing acute renal graft rejection
   6. Dose is typically 1gm po bid
9. Photopheresis [20]
   1. Directed at suppressing donor-specific T cell clones in recipient of graft
   2. Peripheral blood is removed and leukocyte poor fraction returned to recipient
   3. Leukocyte-enriched blood is exposed to UV light in presence of methoxsalen
   4. Methoxsalen covalently binds to DNA pyrimdines and other molecules
   5. Exposure of methoxsalen treated dividing cells to UV light causes cell death
   6. Treated leukocyte fraction returned to patient
   7. These treated leukocytes induce an autologous suppressor response mediated by T cells
   8. T suppressor cells target non-exposed T cells of similar immune specificity
   9. Thus, significant and long term graft specific T cell depletion or suppression occurs
   10. Photopheresis + triple drug immunosuppression reduced acute cardiac allograft rejection
10. Belatacept (LEA29Y) [48]
    1. Fusion protein of CTLA-4 and IgFc region
    2. Blocks T cell costimulation by binding CD80 and CD86, preventing interaction with CD28
    3. Assessed in maintenance therapy versus CsA for renal transplantation
    4. Induction with basilizimab, mycophenolate, glucocorticoids then maintenance therapy
    5. Similar acute rejection rate (7%) at 7 months for belatacept versus CsA
    6. Chronic allograft nephropathy, renal function better with belatacept versus CsA at 1 year
11. Newer Agents [3,10,13,23]
    1. Blockade of major accessory T stimulator molecules: Anti-CD28, Anti-CD2 (LFA3-Fc)
    2. Anti-T cell Abs conjugated to toxins (including Cholera A chain, Pseudomonas)
    3. Establishing microchimerism between recipient and donor cells may prolong survival
    4. Goal is generally induction of tolerance
    5. Use of anti-T costimulator agents may reduce or halt chronic graft rejection [23,34]
12. Significantly increased and similar risk of cancer, including types, in transplant recipients and HIV/AIDS infected persons [50]

K. Graft Versus Host Disease (GVHD)

1. Immune reaction of doner lymphocytes against host tissues causing clinical symptoms [21]
   1. This is a donor T-cell mediated reaction
   2. Involves Class I and probably Class II MHC restricted T lymphocytes
   3. T cell depleted stem cells will engraft without GVHD even with HLA mismatch [25]
   4. Chronic GVHD due to graft cytotoxic T lymphocytes (CTL) killing host endothelial cells, leading to microvessel damage and loss
2. Requirements for GVDH
   1. Graft is immunologically competent
   2. Host has transplant antigens
   3. Host not rejected graft
   4. Mismatches at HLA-A and HLA-C, but not HLA-D associated with GVHD [17]
   5. Ex vivo deplation of alloreactive T cells using anti-CD25 Abs leads to reduced risk of GVHD and no cases of severe (Grade III or IV) GHVD [24]
3. Occurs 2 weeks to 3 months after transplant
4. Symptoms of Acute GVHD
   1. Skin: erythematous rash
   2. Skin vacuolization of basal cell layer and dyskeratosis
   3. Skin infliltrate of small lymphocytes primarilly in epidermis, predominantly CTL
   4. Liver: Elevated liver function tests
   5. Intestinal injury: focal necrosis in intestinal crypts; lost plasma cells, increased PMNs
5. Mortality:
   1. Gram negative sepsis
   2. Opportunistic Infections including cytomegalovirus (CMV), fungal disease
   3. Intestinal hemorrhage
   4. HLA-A but not HLA-D mismatches were associated with mortality after tranpslant [17]
6. Treatment of Acute GVHD
   1. Glucocorticoids
   2. Cyclosporin A
   3. Azathioprene or mycophenolate
   4. Anti-T cell monoclonal antibodies (see above)
   5. In patients with severe, steroid-resistant acute GVHD after allogeneic transplant, infusion of mesenchymal stem cells from allogeneic source improved overall survival at 1 and 2 years [51]
7. Chronic GVHD
   1. Develops 3-18 months post transplant
   2. May be related to injury from the thymus
   3. Develop multi-system autoimmune disease including
   4. Skin and mucous membranes - vitiligo, alopecia, scleroderma-like disease, others
   5. Salivary glands - keratoconjunctivitis
   6. Chronic hepatitis: mixed cell infiltrate
   7. Lung dysfunction

L. Infection Prevention in Organ Transplants [11]

1. Prophylactic antibiotic therapy is most effective for non-viral illness
   1. Essentially all patients receive trimethoprim -sulfamethoxazole (TMP/SMX)
   2. TMP/SMX (Bactrim®, Septra®, others): single strength (80mg/400mg) once daily
   3. reduces pneumocystis, urinary tract infections, listeria, nocardia and toxoplasma
2. Patients at risk for CMV disease: low-dose ganciclovir or valganciclovir prophylaxis
3. Patients at risk for disseminated toxoplasmosis receive pyramethamine and a sulfonamide
4. Vaccinations [38]
   1. Immunizations / boosters should not be done during first 6 months after transplant
   2. When possible, appropriate booster immunizations should be done prior to transplant
   3. Liver virus vaccines are not generally recommended in solid organ transplant recipients
   4. Standard initial immunizations are discussed in "Vaccinations" outline
   5. Booster recommendations are provided here (delay until >6 months after transplant)
   6. Tetanus/Diphtheria - booster every 10 years
   7. Poliomyelitis - inactivated polio vaccine (IPV), boost if low antibody (Ab) titer
   8. Influenza - single dose each year at beginning of influenza season
   9. Hepatitis B virus (HBV) - boost if Ab levels <10IU/L (1-3 doses for booster)
   10. Hepatitis A virus (HAV) - boost if Ab levels low; prophylaxis with Ig if non-responder
   11. Pneumococcus - single dose standard, boost every 6 years
   12. Haemophilus influenza type B - single dose sufficient, unclear benefit of booster
   13. Varicella zoster virus (VZV) - measure serum Ab levels after transplant; booster may be safe but unknown; VZV immune globulin given for low titers after exposure
   14. Measles/Mumps/Rubella (MMR) - vaccine not used in immunocompromised persons; for exposure to measles, ANY solid organ transplant patient should receive immune globulin

M. Lymphoproliferative Disorders [6]

1. Transplant recipients are at high risk for post-transplant lymphoproliferative disease
2. Related to both tranpslant type and type of immunosuppression
3. Most types of lymphoproliferative disease are typically associated with EBV
   1. Polyclonal B cell or plasma cell hyperplasia
   2. Ploymorphic B-cell hyperplasia and lymphoma (usually monoclonal)
   3. High grade monomorphic B cell lypmhoma
   4. Non-EBV associated hepatosplenic T cell lymphoma (poor prognosis) [7]
   5. Bone marrow failure after transplantation may be associated with human herpesvirus 8 [32]
4. Overall risk is 1-2.5% for various types of solid-organ transplants
   1. Kidney Txp: 1%
   2. Heart or Heart/Lung: 2.4%
   3. Liver Txp: 1%
   4. Pancreas Txp: 0.6%
5. Treatment
   1. In polyclonal disease, reduced immunosuppression with antiviral therapy usually works
   2. High dose acyclovir (800mg po 5X/day), famciclor or valacyclovir
   3. Resistant disease usually treated with multi-agent chemotherapy

N. Malignant Skin Tumors [12]

1. Malignant skin tumors occur in >50% of solid organ transplant patients
2. Types
   1. Squamous cell and basal cell carcinomas are 90% of these tumors
   2. Kaposi's Sarcoma
   3. Melanoma
   4. Neuroendocrine skin carcinoma (Merkel-cell carcinoma)
3. Mean Interval between Transplant and Diagnosis
   1. ~8 years in transplant recipients ~40 year olds
   2. ~3 years in transplant recipients age 60 or older
4. Usually associated with multiple warts and premalignant keratoses
5. Human papillomavirus (HPV) is likely risk factor for squamous cell ca
6. Often more aggressive than in non-immunosuppressed patients
7. Treatment
   1. Superficial tumors: cryotherapy or electrocautery and curettage
   2. Thicker lesions excised with careful assessment of margins
   3. Mohs' micrographic surgery recommended for high risk tumors
   4. Metastases to single lymph node region can be cured by lymphadenectomy

O. Xenotransplantation [36,44]

1. Possible solution to organ supply problem
   1. Pig organs have generally been preferred
   2. Baboon or chimpanzee tissues have been used, but are not practical for larger scale
2. Major immunological and infectious obstacles currently exist
3. Hyperacute rejection due to anti-alpha-galactosyl Abs (see above)
   1. Gene knockouts to delete alpha-galactosyl transferases have been accomplished
   2. Plasmapheresis for removal of host anti-alpha-galactosyl Abs
   3. Expression of human decay accelerating factor on pig organs also improves outcomes
4. Risk of infecious disease transmission
   1. Endogenous retroviruses of particular concern
   2. Porcine endogenous retrovirus (PERV) has been examined
   3. PERV can infect human cells, but no clinical consequences have been documented
   4. FDA requires all porcine transplant experiments to evaluate PERV levels

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