Determination of factors responsible for long-term survival of rat heart allografts
Creators: name: Goodnight, James Edgar
Publisher: name: University of Utah
Year: 2012
Subjects: Heart
Rats

description: Long-term survival of whole organ allografts can be obtained without the use of chronic nonspecific immunosuppression.  Administration of anti-donor antibody or donor antigen to the host or short-term treatment of the  host with anti-lymphocytic serum (ALS) is some of the methods most commonly used to induce this phenomenon.  A steady state is produced in the host in which the allograft appears safe from rejection even though the host retains a capacity to respond to donor antigens and is able to reject allografts from other donors in normal fashion.  The mechanisms underlying this phenomenon have not been completely defined.  In this study, long-term survival of Ag-B compatible rat heart allografts was obtained by short-term treatment of the recipients with ALS.  Graft survival apparently was based on a specific change in the hosts rather than on persistent nonspecific effects of ALS.  The hosts were not fully tolerant in that they were able to reject secondary skin allografts from the heart donor strain, through in a delayed fashion.  The long-surviving heart allografts retained their immunogenicity as they were rejected when retransplanted to new hosts.  The passive transfer of serum from long-term heart graft acceptors to new host receiving fresh allografts delayed rejection by several days.  This effect was seen only with the serum from long-term acceptors suggesting that serum-blocking factors were involved in long-term survival of the heart. allografts.  However, the ability of aboptively transferred lymphoid cell to break tolerance to a heart allograft residing in a classically tolerant host  was tested..  In contrast to normal lymphoid cells, cells from the long-term acceptors were unable to break tolerance, suggesting that a specific cellular tolerance had been induced in this cell population.  Moreover, serum from the long-term acceptors failed to block the breakage of tolerance by normal lymphoid cells.  The overriding factor in obtaining long-term heart allograft survival is a predisposition in a particular host-recipient combination towards an enhancement response.  Inbred rat strains, Fischer (Fi) and Lewis (Le), share the serological Ag-B1 allele and react very weakly in a mixed lymphocyte culture (MLC).  In spite of this apparent identity an Ag-B, these strains differ markedly in their immune responses to histocompatibility antigens from an Ag-B disparate third strain, Marshall (Ma) (Ag-B6).  Fi recipients allowed Ma heart grafts an extended survival where as Le recipients rejected them rapidly.  Fi and Ma showed a weak response to MLC in contrast to a strong response for Le and Ma.  Fi produced antisera in response to Ma which had a relatively high titer of antibody but low cytotoxic activity.  Fi responded to another strain,  Buffalo (Buf) (also Ag-B6), in a similar fashion.  Fi apparently can produce a strong allogeneic response as it was able to reject LBN (Ag-B1/3) heart grafts rapidly.  The low response of Fi and Ma probably was not due to shared antigens between the two strains because Ma heart grafts underwent rapid rejection in Le hosts highly tolerant to Fi.  To explain the contrasting response of Fi and Le to the Ag-B5 disparity, we propose that it is controlled by an immune response gene; that Fi has a low-responding allele and Le has a high responding allele.  The data do the reveal a location for this proposed gene.  The high-responding allele appears to be dominant as Ma heart were rejected rapidly by (Fi X Le)F1 recipients.