Restricted antibody formation to sheep erythrocytes of allogeneic bone marrow chimeras histoincompatible at the K end of the H-2 complex.

Abstract

Employing a new method for allogeneic bone marrow transplantation, irradiation chimeras constructed from various combinations of marrow cells from B10 H-2 recombinant mice and AKR recipients were prepared. Though these chimeras had well-developed populations of T and B cells, they showed strikingly different patterns of responses in the primary antibody formation to sheep erythrocytes (SRBC), a T dependent antigen. These are (a) AKR mice treated with C57BL/10 cells, [B10 leads to AKR] fully H-2 incompatible, and AKR mice treated with B10.A (5R) cells, [5R leads to AKR] I-J,E compatible chimeras that were almost completely unresponsive to SRBC; (b) AKR mice treated with B10.BR cells [BR leads to AKR] fully H-2 compatible, and AKR mice treated with B10 AKM cells, [AKM leads to AKR] chimeras where donor and recipient differed only at H-2D, showed the same number of plaque-forming cells (PFC) as B10 control mice; (c) AKR mice treated with B10.A cells, [B10 leads to AKR] chimeras, where donor and recipient were matched at H-2K-I-E region, showed about one-half the number of PFC as the control mice. From these results we conclude that in allogeneic bone marrow chimeras primary antibody response to T-dependent antigen, such as SRBC, is generated when at least the K end of the H-2 complex is compatible between donor and recipient.

Marrow transplantation from tolerant donors to treat and prevent autoimmune diseases in BXSB mice.

“…This cannot generally be accomplished in allogeneic chimeras across MHC barriers. Further, these animals did not develop the late wasting disease without the usual overt manifestations of GVH reaction described by Rayfield and Brent (13) and also encountered in our laboratory (11).…”

“…Marrow transplantation across major MHC barriers heretofore has introduced complex issues of graft versus host (GVH) reaction, chronic wasting syndrome, and defective interaction of the marrow-derived cells (10)(11)(12)(13). Indeed, fully allogeneic marrow chimeras in autoimmune-susceptible mice from autoimmune-resistant mice have been difficult to produce without producing lethal GVH reaction rather than chimeras between autoimmune-resistant strains.…”

Positive selection of a T-cell subpopulation in the thymus in which it develops.

“…Self-MHC tolerance and self-MHC restriction are not merely determined by the genotype of the T cells but are also selected by the microenvironment (thymus) in which the T cells have been developed (4)(5)(6). The process, known as "thymic education," has been thought to be crucial to generation of a functional T-cell repertoire that is essential to survival.…”

H-2-incompatible bone marrow chimeras produce donor-H-2-restricted Ly-2 suppressor T-cell factor(s).

“…Marrow chimeras were prepared as described (9,10,15). After hematopoietic reconstitution, all were maintained without further manipulation for 6-10 weeks prior to analyses for chimerism and preparation of Ly-2 TsF factors.…”

“…In previous reports (5,(9)(10)(11)(12), it was shown that adaptive differentiation occurs for helper T cells from H-2-incompatible chimeric mice; these cells developed so as to generate primary antibody responses to sheep erythrocytes (SRBC) in combination with cells of recipient H-2 type but not with cells genetically identical to their original MHC. T cells from such chimeras primed with an antigen in vivo were found later to cooperate in vitro also with cells ofdonor type, indicating that there may be two separate stages of T-cell differentiation during which self-restriction specificity is acquired.…”