Liver immunosuppression

Inhibition of immunomodulatory cytokines (Fig. 1) Anti-T-cell receptor antibodies Muromonab (OKT3, Orthoclone ) binds to the CD3 complex of the T-cell receptor and induces depletion of T-lymphocytes. It is applied to prevent acute rejection of kidney, liver, and heart allografts. Rapid side effects (within 30-60 min) include a cytokine release syndrome with fever, flu-like symptoms, and shock. Late side effects include an increased risk of viral and bacterial infections and an increased incidence of lymphproliferative diseases due to immunosuppression. 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

Cyclosporine is a cyclic polypeptide immunosuppressant typically used to prevent organ rejection in transplant patients. Its use is restricted to patients with fulminant or refractory symptoms in patients with active IBD. Significant toxicides associated with cyclosporine are nephrotoxicity, risk of infection, seizures, hypertension, and liver function test abnormalities.1,13,14... 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

The 23-valent pneumococcal polysaccharide vaccine is recommended for use in all adults 65 years of age or older and adults less than 65 years who have medical comorbidities that increase the risk for serious complications from S. pneumoniae infection, such as chronic pulmonary disorders, cardiovascular disease, diabetes mellitus, chronic liver disease, chronic renal failure, functional or anatomic asplenia, and immunosuppressive disorders. Alaskan natives and certain Native American populations are also at increased risk. Children over the age of 2 years may be vaccinated with the 23-valent pneumococcal polysaccharide vaccine if they are at increased risk for invasive S. pneumoniae infections, such as children with sickle cell anemia or those receiving cochlear implants. 

Some deaths. Residues (mg/kg fresh weight) >3 in brain, >10 in clotted heart blood, >6 in kidney, and up to 20 in liver Blood lead concentrations, in mg/L, increased from <0.1 at start to 0.1 after 24 h, 3.2 at 7 days, to 6.8 at 14 days. There were some deaths at day 21 and survivors had 0.6 mg Pb/kg blood FW. All dosed birds had immunosuppressive effects, as seen by lowered hemagglutination titers to sheep red blood cells... 

Normal spleen lymphocyte function Maximum nickel concentrations in tissues (in mg/kg FW) were reached in blood (19.8) and placentas (3.9) 2 h following injection those in liver (4.9), spleen (1.3), and kidneys (56.2) were reached 4 h after injection and maximum concentration in fetal tissues (1.1) was reached after 8 h. Authors estimate that all nickel is excreted in 42 to 84 h Immunosuppression in spleen lymphocyte function LD50 (48 h)... 

Cyclosporine demonstrates immunosuppressive activity by inhibiting the first phase of T-cell activation. It also inhibits release of inflammatory mediators from mast cells, basophils, and polymorphonuclear cells. It is used in the treatment of both cutaneous and arthritis manifestations of severe psoriasis. The usual dose is between 2.5 and 5 mg/kg/day given in two divided doses. Adverse effects include nephrotoxicity, hypertension, hypomagnesemia, hyperkalemia, alterations in liver function tests, elevations of serum lipids, GI intolerance, paresthesias, hypertrichosis, and gingival hyperplasia. Cumulative treatment for more than 2 years may increase the risk of malignancy, including skin cancers and lymphoproliferative disorders. 

Patients with chronic conditions that cause limited immune deficiency (e.g., renal disease, diabetes, liver disease, and asplenia) and who are not receiving immunosuppressants may receive live attenuated and killed vaccines, and toxoids. 

Medical indications Chronic pulmonary disease (excluding asthma) chronic cardiovascular diseases, diabetes mellitus chronic liver diseases, including liver disease as a result of alcohol abuse (e.g., cirrhosis) chronic alcoholism, chronic renal failure or nephrotic syndrome functional or anatomic asplenia (e.g, sickle cell disease or splenectomy [if elective splenectomy is planned, vaccinate at least 2 weeks before surgery]) immunosuppressive conditions and cochlear implants and cerebrospinal fluid leaks. Vaccinate as close to HIV diagnosis as possible. 

The expression level of intestinal MDR1 mRNA has been utilized to the personalized immunosuppressant therapy with tacrolimus in cases of living-donor liver transplantation (LDLT) [84], Tacrolimus shows wide... 

The mechanisms of the influence of the SNS on the induction of CD8+ Tregs are likely directed towards both the activation and function of these cells (fig. 2). Sympathetic neurons are a source of (i) norepinephrine that has strong immunoregulatory effects [35] including the proliferation of liver NKT cells necessary for the initiation of contact sensitivity reactions (ii) immunomodulatory NPY [38] that may promote the production of IFN-y necessary for the function of CD8+ suppressor T cells (see below), and (hi) tissue plasminogen activator (t-PA) [41] that converts plasminogen to plasmin that in turn is an activator of immunosuppressive TGF-(3 [42]. 

After transplantation, immunosuppression must be used to prevent host rejection of the graft liver, usually with prednisone and tacrolimus or cyclosporine. Tacrolimus and cyclosporine are calcineurin inhibitors and require drug level monitoring because of a narrow therapeutic range and significant toxicity, including renal failure and neurotoxicity. 

Liver transplant recipients - Safety and efficacy in liver transplant recipients are unknown. If entecavir treatment is necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function (eg, cyclosporine, tacrolimus), renal function must be carefully monitored before and during treatment with entecavir. 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

Lung transplantation-bronchial anastomotic dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended. 

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