Induction Therapy

CLINICAL IMMUNOSUPPRESSION Immunosuppressive agents are essential to graft survival transplant recipient always have drugs even after years after the surgery Over time, fewer numbers of medications are required Why we take the meds? to prevent graft rejection and treat the complications of nonspecific immunosuppression in transplant recipients Nonspecific MOA of immunosuppressive agents increase rate of infections (particularly viral infections) and malignancy They have toxicities Bcoz of this: agents with more specific MOA are emerging Although tolerance remains the unattained goal of research in transplantation significant improvements in immunosuppressive medication have occurred in the past few years Overall Risks Associated With Immunosuppression Risk for Infection Risk for Malignancy Risk for Cardiovascular Disease Induction Agents Two groups of Immunosuppressive drugs induction therapy –agents used immediately after transplantation (antibody preparations directed at lymphocyte populations) maintenance therapy Currently, five commercially available agents are used primarily for induction: I Two polyclonal antilymphocyte agents II

Two monoclonal antibodies against IL-2R

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Anti-CD20 monoclonal antibody Anti-CD52 monoclonal antibody IVIG

Induction therapy agents – used to treat acute rejection episodes Lymphocyte Depletion Measures – are effective because they deplete the host of lymphocytes – MOA not well understood – antilymphocyte globulin (ALG) and traditional monoclonal antibody therapy act by relatively nonselective lymphocyte depletion or inactivation. – immunosuppression d/t ALG or OKT3 increases risk for opportunistic infection or lymphoma – use of ALG or OKT3 < 3 weeks. I. – – – – – –

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III One monoclonal antibody against CD3 cells

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Three other agents are also being tested experimentally in the perioperative period:

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Antilymphocyte Globulin ALGs are polyclonal sera produced when human lymphocytes are injected into animals Rabbit, goat, and horse antisera are commonly used MOA: against T cell most potent sera Suppression can be partially reversed by T cells, but not by bone marrow cells Interferes with cell-mediated reactions (allograft rejection, tuberculin sensitivity, and the GVH reaction). ALGs can abolish preexisting delayed-type hypersensitivity reactions larger doses prolong the survival of some xenografts ALG has a definite, but lesser effect on T-cell–dependent antibody production Lymphocytes coated with ALG are either lysed or cleared from the

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blood by reticuloendothelial cells in the liver and spleen. Administered prophylactically -during the early post-transplant period or Used to reverse ongoing rejection Results depend on: potent ALG and prolonged administration rather than on a single dose ALG is often used in kidney, pancreas, cardiac, and small bowel transplantation, and bone marrow transplantation and preventing the GVH Toxicity depends on: Cross-reactivity with other tissue antigens Ability of the patient to make antibodies against the foreign protein Toxicity: Anemia, thrombocytopenia and most commonly Allergic reactions to the antiserum

Two ALGs are commercially available 1. horse antithymocyte globulin 2. rabbit antithymocyte globulin (most common) –

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Rabbit antithymocyte globulin higher rejection reversal rate than the horse (more effective) (88% versus 76%) The rabbit antithymocyte globulin has antibodies against CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and HLA class I Both effective in preventing and reversing acute rejection episodes

Monoclonal Antibody 1. OKT3 – immortalized B-cell lines that each secrete a single, or monoclonal, antibody in limitless supply – monoclonal antibodies generated against T cells (OKT3, anti-CD3) and – various T-cell subsets (OKT4, antiCD4; OKT8, anti-CD8)

OKT3 – first administered clinically in 1980 – used to treat established episodes of acute kidney, liver, heart, or heart-lung rejection – OKT3 binds to a site associated with the TCR (CD3) and functions to modulate the receptor and inactivate T-cell function. – OKT3 blocks not only the function of naïve T cells but also the function of established CTLs – thereby blocking cell-mediated cytotoxicity – OKT3 blocks the T-cell effector functions involved in allograft rejection MOA: IV administration OKT3 binds to T cells  TCR complex is internalized (no longer expressed on the cell surface)T cells are then removed by the reticuloendothelial cells (liver & spleen) Circulating T cells decrease (30-60 min) – when OKT3 is stopped, CD3+ cells rapidly return to normal levels, because of re-expression of the TCR complex Limitations to OKT3: – immunogenic – can elicit immune reactions – with prolonged use,becomes less effective – An acute cytokine release syndrome can also be seen, usually with the first or second dose ○ administration of steroids or indomethacin can ameliorate this problem. Because of these problems, rabbit antithymocyte globulin has essentially replaced the use of OKT3 at many centers. 2. Interleukin-2 Receptor Inhibitors – The IL-2R is a complex of several transmembrane polypeptide chains – Three IL-2R binding chains: a. a (CD25, 55 kd) b. b (75 kd) c. g (64 kd)

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Noncovalent association of these chains forms the high-affinity binding site for IL-2 – The a chain (IL-2Ra) is present only on activated T cells and a subset of activated B cells and APCs. – Thus, anti-CD25 monoclonal antibody treatment targets the population of lymphocytes enriched for antigen-activated T cells. – These monoclonal antibodies: a. basiliximab (chimeric anti-CD25 monoclonal antibody) b. daclizumab, (humanized antiCD25 monoclonal antibody) – decrease rejection by binding to IL2R without activating it, thus leaving the cell with no free receptors for IL-2 to bind – decrease in acute rejection without increase in infections or malignancy – Both, well tolerated and administered via IV – used in conjunction with other immunosuppressive drugs. 3. Anti-CD20 Monoclonal Antibody (Rituximab) Rituximab - used as an anti-PTLD agent – depletes B cells – CD20 is a surface molecule expressed on B-cells – decrease antibody production in recipients with high panel-reactive antibody (PRA) – part of positive crossmatch protocols – used to treat humoral rejection in cardiac recipients. 4. Anti-CD52 Monoclonal Antibody (Alemtuzumab [Campath 1H]) Alemtuzumab- humanized monoclonal antibody against CD52 – expressed on B cells, T cells, monocytes, and macrophages – results: prolonged depletion of lymphocytes lasts 2 to 6 months – for treatment of lymphoid malignancies, rheumatoid arthritis, and multiple sclerosis.

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lung transplant rejection and as an induction agent in small bowel transplantation with tacrolimus and MMF (and other monotherapies), prevents rejection in renal allograft Benefit of lymphodepletion is that it is often steroid sparing alemtuzumab-treated recipients remain unresponsive to donor antigen even after their T lymphocytes return Intravenous Immunoglobulin (IVIG) from pooled plasma of thousands of donors contains all the antibodies normally found in humans modulate the immune system by; neutralization of circulating autoantibodies by anti-idiotypes and selective down-regulation of antibody production regulate production of T-cell cytokines, inhibit lymphocyte proliferation, and regulate apoptosis. Tx: Desensitization of sensitized recipients with high PRA titers positive crossmatch and ABO-incompatible protocols used in combination with plasmapheresis successfully treated humoral rejection in all types of organ transplants, including some rejection episodes resistant to steroids and antithymocyte globulin Maintenance Agents A general rule in the management of immunosuppression is that the greatest amount of drug is required early after transplantation slowly tapered after the transplant unusual for a transplant recipient to become drug free

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daily immunosuppression with oral pharmaceuticals Prednisone and azathioprine have been used for many years

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Maintenance Agents Adrenal Corticosteroid Prednisone Antiproliferative Agents Azathioprine Mycophenolate mofetil Leflunomide T-Cell–Directed Immunosuppressants Calcineurin inhibitors: cyclosporine, tacrolimus Cell cycle arrest: sirolimus Lymphocyte Sequestration FTY720 1. Adrenal Corticosteroids – widely used as immunosuppressive agents – inhibition of cytokine gene transcription in macrophages, – inhibition of cytokine secretion (IL-1, IL-6, TNF) – suppress the production and effect of T-cell cytokines – Thus, IL-2 production and binding of IL-2 to its receptor are inhibited by glucocorticoids. – inhibition of delayed-type hypersensitivity reactions – suppression of prostaglandin synthesis. – little net effect on antibody production. Cortisone – suppress allograft rejection – prolonged skin graft survival in rabbits – not effective by themselves – in high doses, interrupts rejection reactions

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prolonged use leads to unacceptable side effects such as hypertension, weight gain, peptic ulcers and gastrointestinal bleeding, euphoric personality changes, cataract formation, hyperglycemia that could progress to diabetes, pancreatitis, muscle wasting, and osteoporosis with avascular necrosis of the femoral head and other bones Susceptibility to pyogenic and opportunistic infections Cushingoid features Current protocols, many using rabbit antithymocyte globulin or anti-CD52, or both, for induction and less than 7 days of steroids, have had much better results. Antiproliferative Agents inhibit full expression of the immune response prevents differentiation and division of immunocompetent lymphocytes after their encounter with antigen either structurally resemble essential metabolites or combine with certain cellular components, such as DNA, and thereby interfere with molecular function. Azathioprine Mycophenolate Mofetil Leflunomide Cyclosporine Tacrolimus Sirolimus

g. Tacrolimus h. Sirolimus Co-stimulation Blockade – studies using parenteral immunosuppression for maintenance therapy are now under way – Compliance with multidrug regimens has always been problematic, with late rejection episodes often being associated

with noncompliance with immunosuppression – Parenteral administration at the transplant center would allow physicians to be assured that medications had been received. Belatacept is a selective co-stimulation blockade agent currently in phase III clinical trials. It is a fusion protein of the extracellular portion of CTLA-4 and the constant region fragment of human IgG1 Local Immunosuppression – use of local drug administration systems to establish a more selective presence of immunosuppressive agents in the transplanted organ – Experimental drug-targeting approaches include intra-arterial drug infusion, implantable infusion pumps, controlled-release matrices, drug-impregnated polymer rods, liposomes, topical application (skin or cornea), and aerosol inhalation (lung – used only in composite tissue allotransplant recipients in whom topical immunosuppression is added to systemic immunosuppression to boost levels to the skin Sensitized Recipients – Previous transfusion, pregnancy, ventricular assist devices, and prior transplantation can sensitize individuals – These preformed antibodies can result in hyperacute rejection of transplanted organs – combinations of plasmapheresis, IVIG, splenectomy, and anti-CD20 monoclonal antibodies, combined with conventional immunosuppression, have been developed to allow successful transplantation in these otherwise untransplantable individuals

Individualized Immunosuppressive Regimens – In the past, immunosuppression was a “one-size-fits-all” approach – Most allograft recipients received an induction agent consisting of either ALG or OKT3, followed by cyclosporine, azathioprine, and prednisone as triple-drug maintenance therapy **Tolerance, or a drug-free state, remains the long-term goal in transplantation*** Treatment of Acute Rejection – Although there is debate about the most appropriate agents and the duration of therapy in the treatment of acute rejection, there is little debate over the importance of a prompt and accurate diagnosis, which usually requires biopsy. – therapy is tailored to the degree of rejection – Mild rejections are usually treated with high-dose methylprednisolone with or without a subsequent oral prednisone taper – Mild liver allograft rejection is often treated with increased tacrolimus doses – Moderate to severe rejection is treated with either rabbit antithymocyte globulin or the monoclonal antibody OKT3; failing that, alemtuzumab, rituximab, and IVIG have all been used with some success – CMV prophylaxis with ganciclovir or valganciclovir is generally administered concurrently with therapy for acute rejection