The Role of Interleukin-4 in the Induction Phase of Allogeneic Neonatal Tolerance1,2

Abstract

We previously reported that prolonged graft survival in neonatally tolerant mice was associated with enhanced Th2/Th1 cytokines. To determine whether Th2 CD4 cells function in tolerance, we examined whether we could prevent tolerance by blocking Th2 CD4 maturation, using anti-interleukin (IL)-4 monoclonal antibody treatment during neonatal antigen exposure. Anti-IL-4 treatment restored the ability BALB/c of mice to reject A/J skin grafts and blocked the induction of tolerance through multiple mechanisms. Anti-IL-4 treatment blocked the development of donor microchimerism and recovered the ability of mice to proliferate and to generate appropriate delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses against A/J in a dose-dependent manner. Low-dose anti-IL-4 recovered DTH responses and interferon (IFN)-gamma production, but failed to completely prevent IL-4 production or to recover the CTL activity. No A/J-reactive IFN-gamma-producing CD8 cells were detected in these mice. In contrast, mice treated with higher doses of anti-IL-4 generated normal CTL responses against A/J, and contained A/J-reactive IFN-gamma-producing CD8 cells. The recovery of CTL responses and IFN-gamma-producing CD8 cells was associated with a more complete blocking of Th2 cytokine production. Therefore, the presence of IL-4 may play an important role in the induction of neonatal tolerance by shifting maturation of CD4 cells toward Th2 cells and away from Th1 cells, and also by preventing maturation of alloreactive CD8 CTL cells.

The Primary Responses of Murine Neonatal Lymph Node CD4+ Cells are Th2‐skewed and are Sufficient for the Development of Th2‐biased Memory

“…(Schurmans et al, 1990;Donckier et al, 1995;Gao et al, 1996). Together with our splenectomy experiments, this would suggest that Th2 dominance must be established during primary responses in the lymph nodes.…”

“…It has been shown that IL-4 production in vivo is necessary for the induction and maintenance of neonatally induced tolerance to semiallogeneic F1 cells (Schurmans et al, 1990;Donckier et al, 1995;Gao et al, 1996). Thus, we next tested whether the splenic Th2 dominant responses are required for the induction of tolerance to alloantigens.…”

“…or i.v. with allogeneic cells subsequently reject, in a Th2-dependent manner, donor origin skin grafts transplanted to the tail in later adult life (Goldman et al, 1989;Schurmans et al, 1990;Chen et al, 1995;Donckier et al, 1995;Gao et al, 1996). How these Th2 dominant responses originally arise is, at present, unclear.…”

“…In normal neonates, Th2 responses have been shown to dominate in this transplantation model (Goldman et al, 1989;Schurmans et al, 1990;Chen et al, 1995;Donckier et al, 1995;Gao et al, 1996). To determine whether exclusive Th2 responses also developed in the absence of the spleen, the Th1/Th2 recall responses of lymph node cells from the same animals were monitored in vitro 49 days after the initial skin grafting.…”

Modulation of Tissue-Specific Immune Response to Cardiac Myosin Can Prolong Survival of Allogeneic Heart Transplants

“…To test this, we blocked in vivo IL-4 cytokine that serves as a growth and differentiation factor for Th2 cells (21). IL-4 was neutralized at the time of activation of type 2 CMspecific T cells using a protocol previously described by others (22). Recipient A.TL mice were injected i.p.…”