The objective of this proposal is to dissect the little known mechanism(s), underlying murine natural resistance to normal and malignant hemopoietic cells, which paradoxically manifests itself in F1 hybrid recipients of parental grafts (hybrid resistance) and is mediated by natural killer (NK) cell-like effectors. The expression of the putative target cell surface structure and its recognition by the effectors, are immunogenetically specific and controlled by a class of seemingly """"""""noncodominant"""""""" genes of limited polymorphism, i.e., the Hh (for hemopoietic histocompatibility) genes. It is the primary purpose of the proposed study to apply the techniques of molecular genetics to understand the genetic basis of hybrid resistance controlled by one of the Hh loci, the Hh-1, that maps to the H-2D region of the 17th chromosome. Two alternative hypotheses that may explain the """"""""noncodominance"""""""" will be tested primarily by DNA-mediated gene transfer; a cis-acting mechanism of noncodominant expression would be supported if a Hh-1- phenotype is converted to a Hh-1+ phenotype by transfecting a Hh-1- cell with DNA from Hh-1+ strain of mouse, whereas a trans-acting genetic mechanism of noncodominance would be implicated if Hh-1 expression is suppressed by transfer of a DNA molecule from a Hh-1- strain into a Hh-1+ cell. With this approach, the H-2D region gene encoding or regulating the expression of Hh-1-controlled structures can be identified and isolated. Ultimately, the nature of these cell surface target structures, their expression and function in normal and abnormal (leukemic) hemopoiesis, and a physiological role of Nk-like cells recognizing such structures, may be defined. This study, therefore, should help unravel an important, possibly regulatory, function of the major histocompatibility complex and true functions of a class of lymphoid cells, i.e., the NK cells.
| Kaminsky, S G; Yoshida, M A; Milisauskas, V K et al. (1992) Hemopoietic histocompatibility (Hh-1) phenotype and the regulation of its expression. Immunogenetics 35:117-25 |
| Wroblewski, J M; Kaminsky, S G; Milisauskas, V K et al. (1990) The B144-H-2Db interval and the location of a mouse homologue of the human D6S81E locus. Immunogenetics 32:200-4 |
| Shimamura, K; Kaminsky, S G; Nakamura, I (1989) Acute rejection of allogeneic hemopoietic progenitors by genetically resistant mice. Eur J Immunol 19:1165-70 |
| DeNardin, A M; Brentjens, J R; Andres, G A et al. (1989) Induction of long-term transplantation tolerance, chimerism, and host-versus-graft disease: interrelationship and cellular requirements. Transplant Proc 21:265-6 |
| Milisauskas, V K; Kaminsky, S G; Nakamura, I (1987) Class I H-2Db determinants are not involved in hybrid resistance to parental H-2b/Hh-1b bone marrow allograft. Eur J Immunol 17:1043-9 |
