       Document 0018
 DOCN  M9610018
 TI    Major injury leads to predominance of the T helper-2 lymphocyte
       phenotype and diminished interleukin-12 production associated with
       decreased resistance to infection.
 DT    9601
 AU    O'Sullivan ST; Lederer JA; Horgan AF; Chin DH; Mannick JA; Rodrick ML;
       Department of Surgery, Harvard Medical School, Boston,; Massachusetts,
       USA.
 SO    Ann Surg. 1995 Oct;222(4):482-90; discussion 490-2. Unique Identifier :
       AIDSLINE MED/96025119
 AB    OBJECTIVE: Patients with serious traumatic injury and major burns and an
       animal model of burn injury were studied to determine the effect of
       injury on the production of cytokines typical of the T helper-2
       lymphocyte phenotype as opposed to the T helper-1 phenotype and on the
       production of interleukin-12. SUMMARY BACKGROUND DATA: Perturbations of
       natural and adoptive immunity are related to the increased
       susceptibility to infection manifested by seriously injured and burn
       patients. Earlier work has shown that impaired adoptive immunity after
       injury is characterized by diminished production of interleukin-2
       (IL-2), a product of Th lymphocytes. Exposure of naive Th cells to
       certain antigens and cytokines causes conversion to either the Th-1 or
       the Th-2 phenotype. Th-1 cells produce IL-2 and interferon-gamma
       (IFN-tau) and initiate cellular immunity. Th-2 cells secrete
       interleukin-4 (IL-4) and interleukin-10 (IL-10) and stimulate production
       of certain antibodies. Conversion to the Th-1 phenotype is facilitated
       by IL-12, and conversion to the Th-2 phenotype is promoted by IL-4. The
       authors believed that serious injury might cause conversion of Th cells
       to the Th-2 as opposed to the Th-1 phenotype rather than generalized Th
       suppression. METHODS: The authors studied circulating peripheral blood
       mononuclear cells (PBMC) from 16 major burn and 8 trauma patients on 32
       occasions early after injury and from 13 age- and sex-matched healthy
       individuals for cytokine production after phytohemagglutinin
       stimulation. Also studied was a mouse model of 20% burn injury known to
       mimic the immune abnormalities seen in humans with burns. Splenocytes
       from burn mice, 10 to 12 per group, were studied after activation by
       concanavalin A or by the bacterial antigen Staphylococcus aureus Cowan
       strain I for cytokine production and cytokine messenger RNA expression
       as determined by reverse transcriptase polymerase chain reaction. Burn
       mice were compared with sham-burn controls and attention was focused on
       day 10 after burn injury, a time when IL-2 production and resistance to
       infection are highly suppressed. Finally, burn and sham-burn animals, 20
       per group, were treated in vivo with IL-12 (25 ng daily for 5 days) and
       observed for mortality after septic challenge (cecal ligation and
       puncture [CLP]) performed on day 10 after injury. RESULTS: Peripheral
       blood mononuclear cells from burn and trauma patients produced less
       IFN-tau, the index cytokine of Th-1 cells, than PBMCs from healthy
       individuals 1 to 14 days after burn injury (SE = 77.6 +/- 16 pg/mL
       patients vs. 141.3 +/- 35 pg/mL controls, p < 0.05). However, production
       of IL-4, the index cytokine of Th-2 cells, by patient PBMCs was
       increased (51.0 +/- 13.0 pg/mL patients vs. 26.9 +/- 2.5 controls, p <
       0.05). Splenocytes from mice 10 days after burn injury, when compared
       with sham-burn controls, showed diminished production of IL-2 (1.04 +/-
       0.91 units/mL burns vs. 5.8 +/- 0.55 units/mL controls, p < 0.05) and
       IFN-tau (1.05 +/- 0.7 units/mL burns vs. 12.0 +/- 8.9 units/mL controls,
       p < 0.05). However, burn splenocytes produced more IL-4 (2492 +/- 157.0
       pg/mL burns vs. 672.0 +/- 22.7 pg/mL controls, p < 0.01) and IL-10
       (695.2 +/- 20.8 pg/mL burns vs. 567.0 +/- 16.7 pg/mL controls, p <
       0.05). Splenocyte production of IL-12 was also reduced after burn (0.20
       +/- 0.035 units/mL) as compared with sham burn (0.46 +/- 0.08 units/mL,
       p < 0.05). The reduction in IL-2, IFN-tau, and IL-12 production by burn
       splenocytes was reflected by a tenfold decrease in expression of their
       respective cytokine mRNAs. In vivo IL-12 treatment of burn animals
       decreased mortality from CLP on day 10 after injury from 85% to 15%
       (sham-burn mortality after CLP, 15%, p < 0.05) and increased splenocyte
       IFN-tau production to supranormal levels. (ABSTRACT TRUNCATED)
 DE    Adult  Aged  Animal  Burns/IMMUNOLOGY  Cells, Cultured  Female  Human
       Immunity  Infection/*IMMUNOLOGY  Interferon Type II/BIOSYNTHESIS
       Interleukin-10/BIOSYNTHESIS  Interleukin-12/*BIOSYNTHESIS
       Interleukin-2/BIOSYNTHESIS/PHARMACOLOGY  Interleukin-4/BIOSYNTHESIS
       Leukocytes, Mononuclear/METABOLISM  Lymphocyte Subsets  Lymphocyte
       Transformation  Male  Mice  Mice, Inbred Strains  Middle Age  *Phenotype
       Polymerase Chain Reaction  Spleen/IMMUNOLOGY  Support, Non-U.S. Gov't
       Support, U.S. Gov't, P.H.S.  Th1 Cells/METABOLISM  *Th2 Cells/METABOLISM
       Wounds and Injuries/*IMMUNOLOGY/METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

