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As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]

A positive association has been observed in Igh allotype ‘congenic’ mice between skin graft rejection and a block to effective T-B co-operation in the development of both IgM and IgG responses to sheep erythrocytes. Mismatch of Igh alone is insufficient for such a block to become apparent since pairs of Igh-allotype congenic strains of mice which reciprocally accept skin grafts for at least 5 weeks, show successful positive co-operation (help) between T and B cells. The observed block is manifest both during the education (priming) of T cells in irradiated (first stage) recipients and during co-operation between primed T cells and unprimed B cells in second stage irradiated ‘syngeneic’ recipients. [ABSTRACT FROM AUTHOR]

Inducibility of immunological tolerance to a T-dependent antigen, human serum albumin, was studied in autoimmune mice (NZB, MRL/Mp-1pr/1pr and male BXSB mice), comparing with non-autoimmune mice (BALB/c, DBA/2, MRL/Mp- +/+ and female BXSB mice). Weekly injections of increasing doses of the tolerogen into DBA/2 mice induced T-cell tolerance without the participation of suppressor cells and without affecting B cells. All of the autoimmune mice tested were refractory to the tolerogen; partial tolerance (40%-60% responsiveness) was attained in mice aged 1 month, but not in older mice. By comparison, tolerance was induced in non-autoimmune mice to a similar degree irrespective of the age of the mice. The tolerance inducibility was also examined in reciprocal bone marrow cell (BMC) transfer experiments between NZB and DBA/2 mice and also BMC transfer into B10.D2 mice. It was shown that recipients of NZB BMC were more resistant to tolerance induction than those of DBA/2 BMC, while irradiated NZB mice receiving DBA/2 BMC were susceptible. Hence, it is suggested that the tolerance-resistant nature of the NZB mice was inherent in T-cell precursors in the bone marrow and not in the host environment. Similar findings in support of this notion were also observed in BSXB mice. The significance of tolerance resistance in the development of autoimmunity is discussed. [ABSTRACT FROM AUTHOR]