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A MELISA (Memory Lymphocyte Immunostimulation Assay) test is a blood test that detects type IV hypersensitivity to metals, chemicals, environmental toxins and molds from one single blood sample. The test does not measure toxicity – that is to say, it will not measure the amounts of a harmful substance in the patient's blood. It measures if the patient is allergic to it.

Two articles have concluded that the MELISA test is not useful for diagnosis since a large number of false positive results will be obtained.[1][2] A subsequent study confirmed MELISA as reproducible, sensitive, specific, and reliable for detecting metal sensitivity in metal-sensitive patients.[3]


A MELISA test measures a so-called type-IV delayed hypersensitivity reaction. In contrast to a type-I allergy, which is mediated by IgE antibodies and is often tested using an ELISA test, a type-IV hypersensitivity reaction is mediated by T-lymphocytes (or memory lymphocytes) that have had prior contact with a given allergen.[4] In genetically predisposed individuals, an ongoing everyday exposure to allergens can induce the type-IV hypersensitivity with a resulting allergic reaction.[5]

The test procedure is a cell culture and requires live memory lymphocytes. Lymphocytes are isolated and cultured in an incubator for five days. A portion of the blood is kept intact (unexposed to allergens) to serve as a negative control. A second portion is exposed to a universal allergen, such as Pokeweed, to serve as a positive control. Finally, the third portion of the blood is exposed to the suspected allergen in several different concentrations, to ensure that the conditions in vitro are as similar as possible to the ones in vivo.

As an example, if a patient has a suspected allergy to dental amalgams, then the allergens tested for will be the metals most commonly used in dental amalgams, such as mercury, silver, tin, and copper.[6][7][8] If a patient has a suspected contact allergy to nickel then the test can be used to test for nickel allergy.[9] This is especially useful in individuals who have clinical symptoms (contact dermatitis) but a negative patch test.[10][11] The lymphocyte reaction to such an allergen is measured by two separate technologies: one based on the uptake of a radioactive isotope by dividing lymphocytes (proliferation); the other by classical microscopy evaluation (transformation). The level of reactivity is measured as a Stimulation Index (SI), against the naïve lymphocytes from the unexposed sample (negative control). Viability and reactivity is determined by cell count as well as reaction to the positive control.[12][13]


Occupational medicine[edit]

The MELISA test is used in occupational medicine and environmental health. It has been used to screen workers exposed to metals, chemicals or other allergens in their workplace. This is what the test was developed for originally, at the Astra (now Astra-Zeneca) laboratories in Stockholm, Sweden. In the U.S., a similar technique (LTT) is routinely used to screen for Beryllium allergy in asymptomatic workers exposed to Beryllium dust.[14][15] Other occupations that use sensitivity testing include construction work, mining, electrical work, rubber/wood/ paper/textile industry work, dentistry, hairdressing, and painting.[16] The MELISA test is used to screen, diagnose and monitor the immune response of susceptible or affected individuals.


In Europe, the test is commonly used in dentistry to test for allergy to dental restorative materials, braces and prostheses.[13]

Chronic diseases[edit]

The test is also used to determine whether metal allergy is a factor behind chronic diseases such as chronic fatigue syndrome[17] and multiple sclerosis.[18] The authors hypothesize that if the immune system is constantly staging an allergic reaction to a metal present in the body, this will alert the HPA axis inducing fatigue-like symptoms. A study[19] of 930 fatigue patients showed 62% testing MELISA-positive to metal allergy. Of those who removed the offending metals, 76% improved, but there was no placebo control. Metal allergy is not recognized by scientists as an accepted cause of chronic fatigue syndrome or multiple sclerosis.


To test whether patients with symptoms attributed to dental amalgam differed from healthy controls, a study compared 23 amalgam patients, 30 healthy blood donors with amalgam and 10 healthy subjects without amalgam using MELISA and other tests. The researchers found that a high frequency of positive results was obtained among healthy subjects with or without dental amalgam, and concluded that the test cannot be used as an objective test for mercury allergy.[1]

Another study used 34 patients to test the sensitivity and specificity if the MELISA test, and concluded that it is not useful for diagnosis of contact allergy to the metals gold, palladium and nickel, since a large number of false-positive results will be obtained.[2]

However, according to the MELISA Foundation the studies are flawed, mainly due to the incorrect selection of patients included as well as the use of patch test as a gold standard for the measurement of metal allergy.[20] The clinical relevance of the test has been shown by the decrease of patient-reported metal-specific responses following the removal of the allergy-causing metals (however the trial did not have a placebo control).[21][22]

See also[edit]


  1. ^ a b Cederbrant K, Gunnarsson LG, Hultman P, Norda R, Tibbling-Grahn L (Aug 1999). "In vitro lymphoproliferative assays with HgCl2 cannot identify patients with systemic symptoms attributed to dental amalgam". J Dent Res. 78 (8): 1450–8. doi:10.1177/00220345990780081101. PMID 10439033.
  2. ^ a b Cederbrant K, Hultman P, Marcusson JA, Tibbling L (Mar 1997). "In vitro lymphocyte proliferation as compared to patch test using gold, palladium and nickel". Int Arch Allergy Immunol. 112 (3): 212–7. doi:10.1159/000237456. PMID 9066505.
  3. ^ Valentine-Thon E, Schiawara HW (February–April 2003). "Validity of MELISA for metal sensitivity testing". Neuro Endocrinol Lett. 24 (1–2): 57–64. PMID 12743534.
  4. ^ Stejskal VD, Forsbeck M, Nilsson R (June 1990). "Lymphocyte transformation test for diagnosis of isothiazolinone allergy in man". J Invest Dermatol. 94 (6): 798–802. doi:10.1111/1523-1747.ep12874656. PMID 1693940.
  5. ^ Willis CM, Young E, Brandon DR, Wilkinson JD (September 1986). "Immunopathological and ultrastructural findings in human allergic and irritant contact dermatitis". Br J Dermatol. 115 (3): 305–16. doi:10.1111/j.1365-2133.1986.tb05745.x. PMID 3530310.
  6. ^ Silvennoinen-Kassinen S, Niinimäki A (September 1984). "Gold sensitivity blast transformation". Contact Derm. 11 (3): 156–8. doi:10.1111/j.1600-0536.1984.tb00962.x. PMID 6437738.
  7. ^ Stejskal VD, Forsbeck M, Cederbrant KE, Asteman O (January 1996). "Mercury-specific lymphocytes: an indication of mercury allergy in man". J Clin Immunol. 16 (1): 31–40. doi:10.1007/BF01540970. PMID 8926283.
  8. ^ Marcusson JA (May 1996). "Contact allergies to nickel sulfate, gold sodium thiosulfate and palladium chloride in patients claiming side-effects from dental alloy components". Contact Derm. 34 (5): 320–3. doi:10.1111/j.1600-0536.1996.tb02215.x. PMID 8807223.
  9. ^ Everness KM, Gawkrodger DJ, Botham PA, Hunter JA (March 1990). "The discrimination between nickel-sensitive and non-nickel-sensitive subjects by an in vitro lymphocyte transformation test". Br J Dermatol. 122 (3): 293–8. doi:10.1111/j.1365-2133.1990.tb08276.x. PMID 2322494.
  10. ^ Klas PA, Corey G, Storrs FJ, Chan SC, Hanifin JM (February 1996). "Allergic and irritant patch test reactions and atopic disease". Contact Derm. 34 (2): 121–4. doi:10.1111/j.1600-0536.1996.tb02143.x. PMID 8681540.
  11. ^ Rietschel RL (May 1996). "Reproducibility of patch-test results". Lancet. 347 (9010): 1202. doi:10.1016/S0140-6736(96)90731-X. PMID 8622447.
  12. ^ Sachs B, Merk H (2001). "Demonstration and characterization of drug-specific lymphocyte reactivity in drug allergies". Allergy Clin Immunol Int: J World Allergy Org. 13 (3): 91–8. doi:10.1027/0838-1925.13.3.91. Archived from the original on 2006-10-26.
  13. ^ a b Stejskal VD, Cederbrant K, Lindvall A, Forsbeck M (1994). "MELISA – an in vitro tool for the study of metal allergy". Toxicol in Vitro. 8 (5): 991–1000. doi:10.1016/0887-2333(94)90233-X. PMID 20693060.
  14. ^ Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS (July 1991). "Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease". J Allergy Clin Immunol. 88 (1): 54–60. doi:10.1016/0091-6749(91)90300-D. PMID 2071785. Archived from the original on 2014-08-15.
  15. ^ Newman LS (October 1996). "Significance of the blood beryllium lymphocyte proliferation test". Environ. Health Perspect. 104 (Suppl 5): 953–6. doi:10.2307/3433017. JSTOR 3433017. PMC 1469695. PMID 8933041.
  16. ^ Bach FH, Hirschhorn K (1964). "Lymphocyte interaction: a potential histocompatibility test in vitro". Science. 143 (3608): 813–4. doi:10.1126/science.143.3608.813. PMID 14088078.
  17. ^ Sterzl I, Procházková J, Hrdá P, Bártová J, Matucha P, Stejskal VD (1999). "Mercury and nickel allergy: risk factors in fatigue and autoimmunity". Neuro Endocrinol Lett. 20 (3–4): 221–8. PMID 11462117.
  18. ^ Stejskal VD, Danersund A, Lindvall A, et al. (1999). "Metal-specific lymphocytes: biomarkers of sensitivity in man". Neuro Endocrinol Lett. 20 (5): 289–98. PMID 11460087.
  19. ^ Stejskal VD, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A, Mayer W, Bieger W, Lindh U (1999). "Metal-specific lymphocytes: biomarkers of sensitivity in man". Neuro Endocrinol Lett. 20 (5): 289–298. PMID 11460087.
  20. ^
  21. ^ Stejskal V, Hudecek R, Stejskal J, Sterzl I (2006). "Diagnosis and treatment of metal-induced side-effects". Neuro Endocrinol Lett. 27 (Suppl 1): 7–16. PMID 17261999.
  22. ^ Valentine-Thon E, Müller K, Guzzi G, Kreisel S, Ohnsorge P, Sandkamp M (2006). "LTT-MELISA® is clinically relevant for detecting and monitoring metal sensitivity". Neuro Endocrinol Lett. 27 (Suppl 1): 17–24. PMID 17261998.