Allograft rejection depends on T cell immune responses requiring antigen recognition and costimulatory signals through accessory T cell receptors, including CD28. Inhibition of CD28 signaling with a ...CTLA-4-immunoglobulin (Ig) fusion protein has resulted in immunosuppression and occasional T cell anergy in mouse transplant models, but not in rats. Because this approach also inhibits a potentially tolerizing signal through CTLA-4, selective blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance.
The effects of escalating doses of the rat CD28 monoclonal antibody JJ319 on allograft survival were studied after vascularized heterotopic heart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by flow cytometry.
CD28 antibody JJ319 markedly prolonged cardiac graft survival compared with untreated controls (7 days, range: 6-8). A strictly dose-dependent increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p <0.001) after the administration of 8 x 1 mg JJ319 i.p. (days -1 to +6 before/after transplantation). However, indefinite graft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 receptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed significantly reduced responses to activation.
CD28 antibody JJ319 induces profound immunosuppression after rat heart transplantation, however without development of transplant tolerance. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, there are no qualitative or quantitative differences to the treatment with CTLA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere. Thus, a CD28-modulating approach seems not to allow therapeutic exploitation of a tolerizing signal delivered by CTLA-4 but may still be clinically applicable, especially in combined immune interventions.
The new members of the series of 2,5‐disubstituted DCNQIs, 1d (Cl/OMe), 1e (Br/OMe), 1j (Cl/I), 1k (Br/I), 1l (I/I), form conducting charge‐transfer complexes with TTF (tetrathiofulvalene) which are ...comparable to known DCNQI/TTFs. From these DCNQIs highly conducting radical‐anion salts 2‐X, 5‐Y‐DCNQI2M (M = Li, Na, K, NH4, Tl, Rb, Ag, Cu) can also be prepared either from the DCNQIs and MI (not AgI), on a metal wire (Ag, Cu), or by electrocrystallization (M = Tl, Ag,Cu). For better crystals a method using periodical switching between reduction and partial oxidation has been developed. With CF3 (large, strongly electron‐attracting) as the substituent in DCNQIs 1m (OMe/CF3) and 1n (Me/CF3), conducting TTF complexes remain whereas only 1n yields an insulating copper salt. DCNQI–Cu salts with high conductivities are obtained with alloys containing two or three different DCNQIs. The temperature‐dependent conductivities of DCNQI–M salts (other than copper) are similar to those of metal‐like semiconductors. All new DCNQI–Cu salts are metallic M down to low temperatures, except 1d (Cl/OMe)2Cu which undergoes a sharp phase transition to an insulating stateM → I. By variation of the ligands or their ratios in conducting alloys of DCNQI–Cu salts temperature‐dependent conductivities can be tuned from M → I to M. In addition, alloying three ligands produced for the first time a radical salt with temperature‐independent conductivity from 5 to 300 K. Most remarkably, alloys of the type (2,5‐Me2DCNQI)m Cu/{2,5‐(CD3)2‐DCNQI}n2Cu which exhibit a sharp M → I phase transition on further cooling reenter the conducting state by an I → M transition, with changes of ca. 108 Scm−1 both ways. For the first time in the field of organic metals crystal structures of DCNQI–copper salts have been determined by X‐ray powder diffraction methods and refined by Rietveld analysis. Unit cell data, coordination angles and distances of the π planes are in excellent agreement with the single‐crystal X‐ray data. However, bond lengths and angles of the ligands are to be less accurate. This powder method proves to be most valuable if only microcrystalline material is available.
