INNATE IMMUNITY IN SMALL BOWEL AND HEART TRANSPLANTATION

Abstract

104 NK cells comprise a unique entity of hymphocytes which act as an important effector arm of the innate immune response. Nevertheless NK cells are able to distinguish non-self MHC-class I molecules on target cells in an allospecific fashion. Target cell recognition of non-self MHC-class I molecules encoded by the RT1.C-locus of the RT1 gene complex induces activation of NK cells without the need of prior sensitization process, an immune mechanism also referred to as allogeneic lymphocyte cytotoxicity (ALC). Small bowel transplantation(SBTx) and heart transplantation (HTx) were performed between intra-MHC-class I disparate rat strain combinations which merely differed at the RT1.C-locus in order to show the impact of NK-related and T cell mediated immune responses. Methods: HTx and SBTx was performed in the following rat strain combinations (n=4): (i) LEW.1LM1 (A1B1/D1Clml) → LEW(A1B1/D1C1), (no treatment), (ii) LEW.1LM1 → LEW (recipient treatment with 100μg poly-I:C/kg [NK cell activator], i.p., at d -2,-1 and 0), (iii) LEW.1LM1→LEW (donor treatment with anti-NKR-P1 mAb 3.2.3. 100μl, i.p. at d -2, -1 and 0), (iv) LEW.1R15(A1B1/D1Cu)→LEW, (no treatment), (v) LEW.1R15→LEW (reciepient treatment with 100μg polyI:C at d -2,-1 and 0), (vi) LEW.1R15→LEW (reciepient treatment with 3.2.3 100μl at d-2,-1 and), (vii) LEW.1LV3 (A1B1/D1Clv3)→LEW,(no treatment), (viii) LEW.1LV3→LEW, (recipient treatment with poly-I:C 100μg/kg at d -2,-1 and 0). Flow cytometric analysis and immunohistology was performed from grafts and spleens with a broad panel of mAb including CD4+, CD8+ macrophages, and anti-NKR-P1 mAb 3.2.3. Results: The impact of the non-classical MHC-class I locus RT1. C significantly affected the clinical outcome following HTx and SBTx. Whereas LEW.1R15 donor organs were chronically rejected by LEW recipient rats, LEW.1LM1 donor small bowel grafts (but not hearts) induced lethal GvHD in LEW recipients. GvHD could be abrogated by preoperative depletion of donor(LEW.1LM1) NK cells with mAb 3.2.3. LEW.1LM1 donor organs are never rejected by LEW recipients. LEW.1LV3 donor hearts never induced rejection nor GvHD irrespective of NK-cell modulation. However, in contrast to LEW.1LM1 donor organs LEW.1LV3 donors induced a considerable graft infiltration of recipient NKs but without T cells. Interestingly, chronically rejected organs (LEW.1R15) always displayed a common infiltration of NK and T cells. Conclusions: There is a strong body of evidence that immunogenic eptitopes of the RT1.C locus in the absence of classical MHC class I and II disparities are able to exert strong immune responses which are mainly triggered by donor or host NK cells in the context of GvH and HvG reactions and with apparently tissue-specific differences.