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			The human immune system is a complex set of cells and organs that can be adversely affected by drugs, resulting in increased susceptibility to infections and tumours, allergic responses to drugs, autoimmune reactions, or other forms of immune system disease. The assessment of immunotoxicity is therefore an important component of safety assessment within preclinical toxicology studies.
			The international Immunotoxicity guideline ICH / EMEA / FDA " S8 Immunotoxicity Studies for Human Pharmaceuticals" is now valid from May 2006! This and other recent guidelines from the EMEA (1) and FDA/CDER (2) emphasize the need to assess immunotoxic effects during the preclinical phase of drug development, and recommend specific tests to measure immunotoxicity.
			Comparable guidelines have been issued by regulatory agencies like the OECD or EPA regarding the safety assessment of e.g. chemicals or food additives (3,4), or vaccines (5). According to the EMEA guidelines "all new medicinal products should be tested for their immunotoxic potential". With the ICH-S8 guideline in force now the "should" has been replaced by a "must"!
			For general informations please refer to our dossier " Immunotoxicity and Immunogenicity - Upcoming Changes in the Preclinical Drug Approval Process". NewLab BioQuality has validated and implemented a standardized two-step (tier 1 and tier 2) immunotoxicity testing protocol into its service portfolio which is in full compliance with international guidelines and recommendations. Additional informations to the testing protocols are also available in our dossier Immunotoxicity Testing of Drugs and Chemicals. Phase 1: Screen (Tier 1)   Immunopathology Complete blood count, differential white blood cell count Lymphoid organ weights; Body weight and temperature Histopathology, gross and microscopic (spleen, thymus, lymphnodes, Peyer's patches, and bone marrow)   Humoral immunity Total serum protein, albumin:globulin ratio; Immunoglobulin isotype distribution (IgM, IgG, IgA, IgE) Total haemolytic complement activity Serum autoantibody screen and deposition of immunoglobulins   Cell-mediated immunity Immunostaining and flow-cytometric quantitation of spleen and lymph nodes for B cells and CD4+/CD8+ T cells Mitogen stimulation assays for B and T cells (spleen) Quantitation of resident peritoneal cells and phagocytic ability Phase 2: Comprehensive (Tier 2)   Humoral-mediated immunity Kinetic evaluation of humoral response to T-dependent antigen (primary and secondary responses with sheep red blood cells, or other) Kinetic evaluation of primary humoral response to a T-independent antigen (primary response with bacterial polysaccharides, or other)   Cell-mediated immunity Delayed-type hypersensitivity response to sheep red blood cells, or other Mixed leukocyte response against allogeneic leukocytes (MLR) Cytotoxic T lymphocyte (CTL) cytolysis against allogeneic tumour cells   Host resistance challenge models (endpoints) Syngeneic tumor cells: MethA fibrosarcoma (growth and regression); B16 melanoma (lung burden) Bacterial models: Listeria monocytogenes (mortality); Streptococcus species (mortality) Viral models: Cytomegalovirus (viral load in salivary gland, lung, kidney, spleen, and liver) Phase 1 (tier 1) of our immunotoxicity assessment protocols can be implemented into a standard 28-days repeated dose toxicology study e.g. acc. to guideline OECD 407 using either mice rats. An extension into phase 2 (tier 2) is recommended when immunotoxicity is suggested by data from tier 1 tests, or when the compound to be assessed has an intended immunological area of application. The species of choice for tier 2 studies is the mouse (using rats requires major changes to the host resistance challenge models). Tier 2 requires the immunization/sensitization of additional experimental animals which are not included in a standard 28-days repeated dose toxicology study. (1) Note for Guidance on Repeated Dose Toxicity, CPMP/SWP/1042/99 http://www.emea.eu.int/pdfs/human/swp/104299en.pdf (2) Guidance for Industry: Immunotoxicology Evaluation of Investigational New Drugs, October 2002. http://www.fda.gov/cder/guidance/4945fnl.pdf (3) OECD Guidelines for Testing Chemicals: Repeated Dose Oral Toxicity-Rodent: 28 Day or 14 Day Study (Guideline 407) http://www.oecd.org/dataoecd/17/52/1948386.pdf (4) Health Effects Test Guidelines, Immunotoxicity, OPPTS 870.7800 http://www.epa.gov/opptsfrs/publications/OPPTS_Harmonized/ 870_Health_Effects_Test_Guidelines/Series/ (5) Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines, CPMP/SWP/465/95 http://www.emea.eu.int/pdfs/human/swp/046595en.pdf