Nine patients with clinically diagnosed, radiologically supported primary lateral sclerosis underwent cognitive testing. None was demented, but eight had mild cognitive impairment. Performances were most consistently impaired on neuropsychological tests sensitive to frontal lobe functions, followed by tests sensitive to memory. Cognitive testing may be useful in helping to establish a cortical localization in patients with the syndrome of progressive spasticity. There are potential nosologic relations between primary lateral sclerosis and other degenerative frontal lobe syndromes, such as frontal lobe dementia and progressive spasticity with dementia.
In recent studies (1-3) it has been demonstrated that the passive transfer of imrnunocompetent allogeneic lymphoid cells to guinea pigs previously primed with 2,4-dinitrophenyl-ovalbumin (DNP-OVA) 1 results in the increased synthesis of anti-DNP and anti-OVA antibodies in the absence of further antigenic challenge, and markedly enhances anti-DNP responses to an appropriately timed challenge with DNP coupled to an unrelated carrier, bovine gamma globulin (BGG). This phenomenon has been termed the "allogeneic effect" and has several salient features. First, the phenomenon reflects and requires the development of a transient graftversus-host (GVtt) reaction in the lymphoid organs of the primed host (1). The existence of a concomitant host rejection reaction is not only not required, but appears to play little if any role (3). Secondly, the lymphoid cells of the host must be primed before the administration of allogeneic cells. Numerous attempts to demonstrate an enhanced primary response by the prior administration of allogeneic cells have failed, and, indeed, the primary response is usually suppressed under these circumstances (1-3a). Finally, the allogeneic effect has been shown to replace the requirement for carrier-specific helper T cells in the development of hapten-specific anamnestic antibody responses manifested by the primed lymphoid cells of the host (2).The studies presented in this and the accompanying paper (4) were undertaken in inbred mice to elucidate further the phenomenon of the allogeneic effect, in that, as a model, the mouse provides greater flexibility in manipulating cell populations and histocompatibility differences. In the experiments described here, we show that: (a) the general features of the allogeneic effect
A critical question raised by the initial observations in guinea pigs (1) and in the studies in mice presented in the preceding paper (2) is that of the precise role of the host T cell in the mediation of the allogeneic effect on antibody production. Thus, the phenomenon requires the existence of an active graft-versus-host (GVH) 1 reaction in which the primed B lymphocytes are those of the host cell population. The occurrence of a host rejection reaction is not only not required, but also appears to play little, if any, role (1, 3). This suggests that, by direct action on primed B cells, the allogeneic effect obviates entirely the need for the interaction between isologous T and B lymphocytes specific for the challenging conjugate, or, alternatively, enhances the functional effectiveness of the small number of isologous T cells specific for the second carrier.To approach this issue directly requires a system in which both cell populations, i.e. the 2,4-dinotrophenyl (DNP)-primed population and a population of allogeneic lymphoid cells, are accessible to experimental manipulation such that the T lymphocytes of one or the other can be selectively removed. In the present study, we describe conditions for the elicitation of an allogeneic effect on the adoptive transfer secondary anti-DNP antibody response in mice. Utilizing such a model, we have established that the allogeneic effect on antibody production can operate on a population of primed B lymphocytes which have been depleted of their isologous T lymphocytes. Materials and MethodsThe proteins and hapten-carrier conjugates were identical to those described in the preceding paper (2).
The adoptive transfer of 2,4-dinitrophenyl(DNP)-keyhole limpet hemocyanin(KLH)-primed lymphocytes into a heavily irradiated allogeneic recipient permits the development of a secondary anti-DNP antibody response to DNP-bovine gamma globulin(BGG) whether or not the irradiated allogeneic host possesses BGG-specific helper T cells. This "allogeneic effect" has been demonstrated to result from the capacity of residual, apparently radioresistant, T cells in the irradiated host to exert an active effect on the transferred histoincompatible B lymphocytes. This conclusion derives from two corroborative experiments. In the first, an allogeneic effect was shown to occur on DNP-primed F1 spleen cells that had been adoptively transferred to irradiated parental recipients; the second experiment demonstrated the development of an allogeneic effect on anti-θ-treated, DNP-specific donor cells transferred to irradiated allogeneic hosts. These results emphasize the extreme caution required in designing and interpreting experiments that may involve adoptive cell transfers into histoincompatible hosts, and illustrate why such models are unsuitable for investigation of the question of physiologic cooperative interactions between T and B lymphocytes. Suitable approaches are described in the accompanying paper.
The allogeneic effect has been shown to replace the requirement for carrier-specific helper thymus-derived (T) lymphocytes in secondary antihapten antibody responses in guinea pigs or mice. Attempts to enhance primary antibody responses to either 2,4-dinitrophenyl (DNP)-keyhole limpet hemocyanin (KLH) or DNP-ovalbumin (OVA) by the allogeneic effect have failed, and frequently result in suppression. However, the present studies have demonstrated a clear allogeneic effect on primary anti-DNP responses to a DNP-conjugate of the copolymer of D-glutamic acid and D-lysine, DNP-D-GL. This compound, for which no carrier-specific helper T cells exist, normally induces a state of DNP-specific tolerance in the doses employed. However, normal (BALB/c x A/J)F1 recipients developed primary anti-DNP antibody responses, and of the IgG class, when DNP-D-GL was administered shortly after the transfer of allogeneic parental A strain lymphoid cells. To test the possibility that the presence of KLH-specific T lymphocytes might inhibit the expression of the allogeneic effect on the primary response to DNP-KLH, studies were undertaken using T cell-depleted spleen cells. In this model, the allogeneic effect again enhanced the primary response to DNP-D-GL, but still failed to enhance the primary response to DNP-KLH. These studies indicate that the structure of the molecule employed and its specific interaction with the bone marrow-derived (B) cell membrane may be critical in the capacity of primed and unprimed B cells to be influenced by the allogeneic effect.
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