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E H Field

Publications and source records attributed to E H Field.

At least 19 recordsLinked to original sources
PubMed2001

Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation.

Total lymphoid irradiation (TLI), originally developed as a non-myeloablative treatment for Hodgkin's disease, has been adapted for the induction of immune tolerance to organ allografts in rodents, dogs and non-human primates. Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidney allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marrow cells are transplanted along with the organ allograft. An advantageous feature of TLI for combined marrow and organ transplantation is the protection against graft-versus-host disease (GVHD) and facilitation of chimerism afforded by the predominance of CD4+ NK1.1(+) -like T cells in the irradiated host lymphoid tissues. Recently, a completely post-transplantation TLI regimen has been developed resulting in stable mixed chimerism and tolerance that is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This review summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in the induction of mixed chimerism and protection from GVHD.

Animals↗
PubMed2001

CD4+CD25+ regulatory cells in acquired MHC tolerance.

Tolerance to self-antigens is an ongoing process that begins centrally during T-cell maturation in the thymus and continues throughout the cell's life in the periphery by a network of regulated restraints. Remaining self-reactive T-cells that escape intrathymic deletion may be silenced within the peripheral immune system by specialized regulatory CD4+ cells. By analogy, regulatory CD4+ cells that control immunity to "acquired self" should arise in circumstances where the immune system acquires tolerance to foreign MHC, such as the tolerance that develops following the exposure to foreign MHC antigens during the neonatal period. We have used this classic model of neonatal tolerance to examine the role of regulatory CD4+ cells in acquired tolerance to disparate class I and class II MHC. Adoptive transfer of unfractionated but not CD4+-depleted spleen cells from neonatal tolerant mice into SCID recipients inhibited skin graft rejection by immunocompetent CD8+ T cells. Using 5-bromo-2'-deoxyuridine incorporation, standard cytotoxic T-lymphocyte assays, short-term interferon-gamma ELISPOT, and intracellular FACS analysis to study CD8+ T-cell effector function, we demonstrated that neonatal tolerant mice contain CD4+CD25+ cells that suppress the development of anti-donor CD8+ T-cell responses in vitro. We conclude that regulatory CD4+CD25+ cells initiate and/or maintain tolerance by preventing the development of CD8+ T-cell alloreactivity.

Animals↗
PubMed1999

CD4+CD25+ cells regulate CD8 cell anergy in neonatal tolerant mice.

BACKGROUND: Injection of neonatal BALB/c mice with semi-allogeneic splenocytes leads to antigen-specific tolerance lasting into adulthood. Tolerant mice accept A/J skin grafts and fail to generate CD8 cytotoxic T lymphocyte (CTL) activity against A/J targets. Anergic CD8 T cells are present in tolerant mice, and CD4 regulatory cells function to maintain CD8 cell anergy. METHODS: Neonatal BALB/c mice were injected with 108 live CAF, splenocytes, and mice were deemed tolerant by accepting A/J grafts over 40 days. CD8 cell proliferation was measured by in vitro incorporation of bromodeoxyuridine coupled with fluorescence-activated cell sorter analysis. Alloantigen-specific cytotoxicity was tested using 51Cr release assays of A/J or third-party targets. RESULTS: We demonstrate that A/J-specific anergic CD8 cells are present in neonatal primed mice that develop tolerance but not in neonatal primed mice that reject A/J skin grafts. Anergic CD8 cells show decreased proliferation and no CTL activity against A/J targets. Addition of interleukin-2 (IL-2) to unfractionated cultures fails to restore CTL activity against A/J targets. However, addition of IL-2 to CD4-depleted cultures restores A/J-specific CD8 CTL activity. Removal of CD4+/CD25+ cells, but not CD4+/CD25- cells, also restores CD8 CTL activity against A/J in the presence, but not the absence, of IL-2. Moreover, when added back into cultures, purified CD4+/CD25+ cells from tolerant mice inhibit the generation of CD8 CTL against A/J targets. CONCLUSION: These data indicate that CD8 anergy is associated with the state of tolerance, and that CD4+CD25+ cells from tolerant mice function to maintain A/J-specific CD8 cell anergy in vitro.

Animals↗
PubMed1998

CD4 regulatory cells in immune tolerance.

We have used the classic model of neonatal tolerance to investigate the hypothesis that acquired tolerance depends on the generation of regulatory CD4 cells. Injection of neonatal BALB/c mice with semi-allogeneic CAF1 (BALB/c X A/J) spleen cells induces antigen-specific tolerance (TOL) in 80% of mice. TOL mice accept fully allogeneic A/J skin grafts for >60 days. TOL mice show diminished Th1 CD4 and CD8 cell immunity against A/J in vitro. In contrast, TOL mice show increased levels of anti-A/J Th2 CD4 responses. Thus tolerance is associated with the inhibition of Th1 CD4 and TC1 CD8 responses and the enhancement of Th2 CD4 responses. Because of this relationship, we hypothesized that regulatory Th2 CD4 cells in TOL mice maintain tolerance by blocking activation of A/J-reactive TC1-CD8 cells. Using in vitro BrdU assays to measure CD8 proliferation within unfractionated cell cultures, we showed that CD8 cells from TOL mice proliferate normally to exogenous interleukin-2 (IL-2) but fail to proliferate in response to A/J cells. The addition of exogenous IL-2 does not restore CD8 proliferation to A/J, ruling out simple CD8 cell anergy. However, when CD4 cells are depleted from the cultures, IL-2 could restore the ability of A/J-reactive CD8 cells to proliferate and to secrete IFN-gamma. Thus CD4 cells from TOL mice inhibit IL-2 rescue of "anergic" A/J-reactive CD8 cells. The results demonstrate a novel link between two major mechanisms of tolerance, immunoredirection and anergy.

Animals↗
PubMed1997

Balancing the immune system for tolerance: a case for regulatory CD4 cells.

In the past, tolerance mechanisms have focused on processes that involve elimination (deletion) or paralysis (anergy) of immune responses. It is now becoming clearer that peripheral tolerance to antigen depends on the generation of regulatory cells that function to maintain the tolerant state. The development of peripheral tolerance may require that the immune system utilize several strategies, including deletion, anergy, and immunoregulatory pathways, and these strategies may overlap. Recent investigations using animal models of transplantation tolerance have demonstrated that immunoregulatory CD4 mechanisms may play a central role in limiting organ-destructive immune responses. In this Overview, we discuss the rationale behind the need for invoking active regulatory mechanisms in peripheral immunologic tolerance and summarize the data that support or refute a CD4 regulatory mechanism.

Animals↗
PubMed1997

Association between enhanced Th2/Th1 cytokine profile and donor T-cell chimerism following total lymphoid irradiation.

Total lymphoid irradiated (TLI) mice develop antigen specific tolerance if the initial antigen exposure occurs shortly after the completion of TLI. We injected TLI-treated mice with semiallogeneic donor cells at 2, 7, or 28 days after completing TLI and determined the levels of donor CD4 and CD8 cells 5 to 7 weeks after TLI treatment. The level of chimerism correlated with the timing of the initial alloantigen exposure. Donor CD4 and CD8 cells were noted only in day 2 or 7 injected mice. Because donor cell chimerism suggested increased in vivo survival of donor cells, we used the level of donor cell chimerism as a surrogate marker for tolerance to examine the relationship between the development of tolerance and enhanced Th2/Th1 cytokine responses to donor antigen. Increased levels of donor CD4 and CD8 cells in the TLI-treated mice was associated with increased Th2/Th1 cytokine production and decreased CTL activity to donor antigen in vitro. Higher Th2/Th1 cytokine levels also correlated with lower CTL activity. The results indicate that the increased production of Th2/Th1 may function to enhance survival of donor cells in TLI-treated mice and suggest that tolerance induction after TLI treatment involves immunoredirection.

Animals↗
PubMed1996

The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance.

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.

Animals↗
PubMed1996

Mechanisms of tolerance induction: splenocytes from total lymphoid irradiated mice inhibit the IL-2 pathway in TCR-activated CD4 cells.

Mice given total lymphoid irradiation (TLI) can be tolerized by an incompletely understood mechanism to foreign Ags given during a brief window of time immediately after completing radiation. We previously showed that splenocytes taken from mice immediately after completing TLI treatment (TLI cells) block the ability of control cells to proliferate or to produce IL-2 in response to alloantigen, suggesting that TLI cells interfere with the IL-2 pathway in responder lymphocytes. To further characterize the mechanism by which TLI cells affect IL-2, we utilized an in vitro system of T cell activation. Adding TLI cells into cultures decreased the ability of TCR-stimulated T cells to proliferate and to secrete IL-2 by 40 to 60%. Exogenous IL-2 did not restore the proliferative response. The inhibition of IL-2 secretion resulted both from a decrease in the number of IL-2-producing cells and a decrease in IL-2 mRNA transcription. TLI cells directly inhibited IL-2 secretion by TCR-stimulated CD4 cells, as determined by ELISPOT. Competitive PCR demonstrated that TLI cells decreased IL-2 transcription of TCR-stimulated CD4 cells by 75%. In situ hybridization confirmed that unfractionated spleen and sorted CD4 cells from TCR-stimulated cultures transcribed less IL-2 RNA in the presence of TLI cells. The results show that TLI cells directly inhibit IL-2 transcription and protein secretion of normal TCR-stimulated CD4 cells.

Adoptive Transfer↗
PubMed1996

Prevention of Th1 response is critical for tolerance.

We investigated the role of Th1 ad Th2 cytokines in rejection and tolerance using the neonatal tolerance model. We reported previously that lymph nodes that drained immunogen-bearing tolerant grafts produced a 10- to 100-fold higher ratio of interleukin (IL)-4 to interferon (IFN)-gamma compared with lymph node cells from rejected grafts. Moreover, because neonatal antigen exposure triggers allospecific Th2 CD4 memory cells, whereas antigen exposure during adulthood triggers Th1 CD4 memory cells, we speculated that immunoredirection toward Th2 and away from Th1 functions as another mechanism of tolerance. To test the immunoredirection hypothesis, we examined whether recovery of Th1 cytokine responses abrogates tolerance. We now show that treatment with exogenous IFN-gamma at the time of neonatal priming recovered mixed lymphocyte reaction hypoproliferation and restored the ability of mice to reject skin grafts. Mice that received IFN-gamma at the time of neonatal priming produced more IFN-gamma and contained more A/J-reactive IFN-gamma producing CD4 cells compared with untreated neonatal primed mice, but failed to recover A/J-specific INF-gamma-producing CD8 cells or CTL responses, which suggests that graft rejection occurred via Th1 CD4 cells. Interestingly, draining lymph node cells from rejected grafts in IFN-gamma-treated neonatal primed mice also produced more IL-4, compared with cells from healthy grafts on untreated neonatal primed mice. Nonetheless, lower IL-4 to IFN-gamma ratio predicted graft rejection and higher ratios predicted acceptance. We conclude that neonatal tolerance depends on the ability to block generation of allospecific Th1 responses that lead to rejection. Thus, immunoredirection involves both the inhibition of Th1 and expansion of Th2 immune responses.

Animals↗
PubMed1995

Expansion of memory Th2 cells over Th1 cells in neonatal primed mice.

BALB/c mice primed with CAF1 splenocytes during the neonatal stage developed A/J-specific tolerance with prolonged survival (> 60 days) of A/J skin grafts. Mice failed to develop A/J-specific cytotoxicity, but rejected third-party skin grafts and generated appropriate third-party cytotoxic T cell responses. We demonstrated previously that graft acceptance was associated with enhanced interleukin (IL)-4 and diminished interferon [IFN]-gamma tolerogen-specific cytokine production, whereas third-party graft rejection was associated with the opposite pattern of cytokine production. We now report that neonatal mice do not mount mixed lymphocyte reaction responses against A/J, but the mice contain a higher percentage of IL-4-producing cells that were characterized as CD4+Mel-14lo cells. Although alloantigen priming of both neonatal and adult control mice expands the CD4+Mel-14lo subset, CD4+Mel-14lo cells from neonatal primed mice produce significantly higher levels of IL-4 and IL-10 and lower IFN-gamma, whereas CD4+Mel-14lo cells from adult primed mice produce mainly IFN-gamma. Moreover, enzyme-linked spot immunosorption analysis demonstrates that, compared with adult primed mice, neonatal primed mice contain more IL-4-producing CD4 cells and less IFN-gamma-producing cells, which indicates that neonatal antigen exposure induces and expands alloreactive Th2 memory CD4 cells. The addition of neutralizing antibodies against IL-4 and IL-10 to primary MLR failed to recover IFN-gamma by CD4+Mel-14lo cells, but cells secreted IFN-gamma after a second in vitro restimulation with tolerogen, which indicates that CD4 cells from neonatal tolerant mice have the capacity to differentiate into Th1 cells. In summary, neonatal tolerant mice contain higher ratios of Th2/Th1 CD4 cells, and the Th2 cytokines function to maintain the ratio by inhibiting Th1 differentiation.

Animals↗
PubMed1995

CD4 Th2 cells do not functionally suppress CTL generation in neonatal tolerant mice.

Injecting semiallogeneic CAF1 spleen into BALB/c newborn mice renders mice tolerant, and the majority of mice show prolonged survival of tolerogen-bearing A/J skin grafts. Moreover, graft survival is associated with enhanced Th2 cytokine responses and graft rejection with Th1 cytokine responses. To further delineate the mechanisms of tolerance, we evaluated CTL responses and found that 74% of neonatal primed mice failed to generate A/J-specific CTL responses, as determined by standard CTL assays and pTc3 frequency analyses. CTL unresponsiveness coexisted with an enhanced tolerogen-specific Th2 memory cytokine profile; spleen cells from neonatal primed mice secreted more interleukin (IL)-4 and less IL-2 and interferon (IFN)-gamma in MLR cultures compared with either adult primed or naive controls. We therefore examined the hypothesis that enhanced Th2 cytokine levels prevent the generation of tolerogen-specific CTL. Adding neutralizing antibodies to IL-4 and IL-10 recovered IFN-gamma production in vitro but not A/J-specific CTL response. In addition, CD4 cells from neonatal primed mice provided help for primary or secondary CD8 CTL generation, which suggests that the enhanced Th2 cytokine profile does not actively suppress CTL generation. Furthermore, CD4 cells from adult primed mice failed to restore the A/J-specific CD8 CTL generation of neonatal primed mice. The results show that failure to develop A/J-specific CTL reaction occurs without suppression by the enhanced Th2-type responses and imply that either deletion or anergy mechanisms block CTL generation. Therefore, neonatal alloantigen exposure not only shifts the development of alloreactive CD4 cells toward Th2, but also blocks development of alloreactive CD8 CTL in this strain combination.

Animals↗
PubMed1995

Alloantigen priming after total lymphoid irradiation alters alloimmune cytokine responses.

Total lymphoid irradiation (TLI) treatment represents a model of acquired tolerance, as TLI-treated mice develop donor-specific tolerance when exposed to alloantigens shortly after completing TLI. To determine whether immunoredirection plays a role in immunologic tolerance in TLI, we examined whether antigen priming in the immediate post-TLI stage altered the cytokine profile toward Th2. Compared with splenocytes isolated from control primed mice, the splenocytes from TLI-primed mice failed to proliferate to immunogen in mixed leukocyte reaction cultures but proliferated normally to third-party alloantigen. Whole spleen and purified CD4 cells isolated from TLI-primed mice produced more interleukin (IL)-4 and less gamma-interferon (IFN-gamma) in response to immunogen-bearing stimulator cells than controls, resulting in higher IL-4 to IFN-gamma ratios. The CD4 subset from TLI-primed mice contained more IL-4-producing and fewer IFN-gamma-producing cells, suggesting that priming after TLI shifted CD4 maturation toward Th2 cells. Surprisingly, TLI-primed mice contained no immunogen-responsive, IFN-gamma-producing CD8 cells, indicating that priming after TLI abrogated development of this CD8 subset. In summary, the data show that priming in the immediate post-TLI phase shifts the allospecific memory cytokine pattern toward Th2 cytokines by enhancing IL-4-producing CD4 cells and preventing maturation of IFN-gamma-producing CD8 cells. We speculate that the cytokine milieu at the time of antigen priming drives differentiation of the tolerogen-specific immune response toward Th2 cells, because splenocytes isolated immediately after TLI produced high levels of IL-4 and little IL-2. The enhanced Th2 pattern that developed in the TLI-primed mice suggests that immunoredirection may also occur in the TLI model of tolerance.

Animals↗
PubMed1995

Enhanced type 2 and diminished type 1 cytokines in neonatal tolerance.

We examined the cytokine profiles associated with tolerance and rejection using the mouse model of neonatal tolerance. BALB/c mice primed with CAF1 splenocytes during the neonatal stage showed increased A/J skin graft survival of > 60 days and failed to develop anti-A/J cytotoxic responses, but rejected third-party C57BL/6 grafts. Lymph node cells that drained A/J grafts on neonatal-primed mice produced allospecific immune cytokine responses characterized by high IL-4 and low IFN-gamma levels. In contrast, lymph node cells that drained either rejected third-party grafts or rejected A/J grafts placed on adult controls produced less IL-4 and more IFN-gamma. Tolerogen-specific immune responses from neonatal-primed mice made up to 100 times higher IL-4 to IFN-gamma ratios than did controls. Alloantigen priming during the immediate neonatal stage induced constitutive expression of IL-4 mRNA in the spleen without IFN-gamma mRNA, whereas alloantigen stimulation during adulthood induced the opposite pattern. IL-4 production from neonatal primed mice was confined to the CD4 population. The altered cytokine profile of enhanced IL-4/IFN-gamma in neonatal primed mice persisted for up to 12 weeks after priming in in vitro secondary MLR assays, which suggests that the initial timing of antigen stimulation critically influenced CD4 maturation. The results support a model of immunoredirection as a mechanism of tolerance and provide rationale for examining the therapeutic use of cytokines in transplantation.

Aging↗
PubMed1994

Effect of anti-CD4 on CD4 subsets. I. Anti-CD4 preferentially deletes resting, naive CD4 cells and spares activated CD4 cells.

Anti-CD4 has been extensively studied in murine models of autoimmunity and transplantation. The timing of anti-CD4 administration in these systems is critical because anti-CD4 effectively blocks primary T-dependent responses but does not diminish ongoing or memory responses in immunized animals. These differential effects suggest that anti-CD4 suppresses a subpopulation of CD4+ cells. We previously observed in vitro that simultaneous activation through TCR-T3 rescued CD4+ cells from anti-CD4 elimination. From this we hypothesized that activated CD4+ cells resisted the effects of anti-CD4. We now show that in vivo treatment with anti-CD4 preferentially eliminated resting, naive CD4+ cells rather than memory and effector CD4+ cells. The CD4+ cells that remained after anti-CD4 treatment exhibited evidence of recent activation, because a higher percentage expressed IL-2R, regardless of subset phenotype. Moreover, Mls-1-primed, anti-CD4-treated mice showed a higher percentage of V beta 6+ (Mls-1 reactive) CD4+ cells than either unprimed mice, anti-CD4-treated mice, or Mls-1-primed controls, implicating the importance of recent activation. These anti-CD4-resistant cells also retained their functional abilities. T cells from BALB/c mice treated with anti-CD4 after Mls-1 immunization maintained their MLR proliferation against DBA/2 stimulator cells. In addition, anti-CD4 did not reduce T-dependent antibody responses in mice previously primed against the Ag cholera toxin or SRBC. Thus, activated CD4+ cells resist the suppressive effects of anti-CD4. Our findings have critical implications for the ongoing clinical trials using anti-CD4.

Animals↗
PubMed1993

Evidence for excessive Th2 CD4+ subset activity in vivo.

Although distinct Th1 and Th2 CD4+ subsets are apparent in in vitro studies, controversy exists over whether these subsets occur functionally in vivo. We describe a patient whose presenting laboratory features of elevated IgG4 and IgE and eosinophilia suggested high levels of IL-4 and IL-5 and in vivo expansion of the CD4+ Th2 subset. Anti-CD3-activated patient PBL induced heightened levels of IgG4 and IgE from normal B cells, indicating that the patient's abnormal Ig isotypes were T cell driven. Stimulated PBL from the patient secreted more IL-4, compared with control PBL, but similar levels of IFN-gamma. Semiquantitative reverse polymerase chain reaction demonstrated that activated PBL from the patient produced higher IL-4 and IL-5, lower IL-2, and similar IFN-gamma mRNA levels, compared with controls. FACS analysis showed that the patient expressed an expanded population of CD4+Leu-8+CD45RA- cells, the memory-effector population, and RNA in situ hybridization confirmed that the CD4+Leu-8+CD45RA- population of the patient was enriched for IL-4-transcribing cells. Moreover, IL-4-transcribing cells outnumbered IFN-gamma-transcribing cells by 2:1 in the memory-effector CD4 population, confirming that Th2 cells exist in vivo within the expanded CD4+Leu-8+CD45RA- population. Taken together, these results provide evidence that Th2 cells exist in vivo and they suggest that the expanded Th2 population produces excessive cytokines that may contribute to the sinopulmonary pathology of the patient.

Base Sequence↗
PubMed1993

Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee.

OBJECTIVE: To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and withdrawal from the trial due to lack of efficacy. METHODS: One hundred seventy-eight patients with OA of the knee were enrolled in a 2-year prospective, controlled, double-blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment. RESULTS: After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50-foot walk time. Sixty-two patients completed the 2-year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%). CONCLUSION: The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.

Acetaminophen↗
PubMed1993

Age influences recovery of systemic and mucosal immune responses following acute depletion of CD4 T cells.

We have examined the influence of recipient age on the recovery of the CD4 T cell compartment following in vivo treatment with anti-CD4. Mice were treated with anti-CD4 beginning in utero (adolescent), at 8 weeks (young adult), or at 52 weeks (old adult). Following acute CD4 depletion, adolescent mice recovered CD4 T cells rapidly (99% of age-matched controls at 5 weeks after anti-CD4 treatment). Young adult mice recovered more slowly (48% of control at 5 weeks), while old adult mice recovered less than 50% of control CD4 T cell numbers at 12 weeks after depletion. At 12 weeks after anti-CD4 treatment, adolescent mice made an enhanced anti-SRBC antibody response and young adult mice mounted a response comparable to their age-matched controls. In comparison, old adult mice mounted on anti-SRBC response that was only 57% that of their age-matched controls. By 1 week after cessation of anti-CD4 treatment, adolescent mice mounted normal systemic and intestinal responses to challenge with the thymic-dependent antigen cholera toxin (CT). In contrast, young adult mice recovered < 50% of age-matched control CT responsiveness by 5 weeks post-CD4 depletion. By 5 weeks post-CD4 depletion, young adult mice exhibited normal tolerance following enteric tolerization with ovalbumin. These findings underscore the importance of recipient age in designing or interpreting studies employing T cell depletion.

Aging↗